Fact-checked by Grok 2 weeks ago

Excitatory synapse

An excitatory synapse is a specialized junction between neurons in the nervous system where the presynaptic neuron releases excitatory neurotransmitters, primarily glutamate in the central nervous system, that bind to receptors on the postsynaptic neuron, triggering an influx of cations such as sodium (Na⁺) and calcium (Ca²⁺), which depolarizes the postsynaptic membrane and increases the probability of generating an action potential.^[1]^[2] This process generates an excitatory postsynaptic potential (EPSP), a graded depolarization that summates with other inputs to potentially reach the action potential threshold, typically around -50 to -40 mV from a resting potential of about -70 mV.^[1]^[3] The mechanism of excitatory synaptic transmission begins with an action potential arriving at the presynaptic terminal, which opens voltage-gated calcium channels, allowing Ca²⁺ influx that promotes the fusion of synaptic vesicles with the presynaptic membrane and release of glutamate into the synaptic cleft—a narrow gap of 20–40 nm.^[3] Glutamate diffuses across the cleft and binds to ionotropic receptors, such as AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methyl-D-aspartate) receptors, on the postsynaptic membrane, opening ligand-gated ion channels permeable to Na⁺ and Ca²⁺ for rapid depolarization.^[1]^[4] Metabotropic glutamate receptors can also modulate slower, longer-lasting effects through second messenger systems.^[5] Excitatory synapses form the foundation of neural communication in the brain, enabling information processing, circuit formation, and plasticity mechanisms essential for learning and memory, such as long-term potentiation (LTP).^[6] They are predominantly glutamatergic in the central nervous system, comprising the majority of synapses, and their dysfunction is implicated in disorders including epilepsy, Alzheimer's disease, and schizophrenia.^[2]^[6] Structurally, excitatory synapses feature a prominent postsynaptic density rich in scaffolding proteins and receptors, which dynamically regulates synaptic strength and efficacy.^[6]

Fundamentals

Definition and Characteristics

An excitatory synapse is a type of chemical junction between neurons in which the presynaptic neuron releases neurotransmitters that bind to receptors on the postsynaptic neuron, causing depolarization and thereby increasing the likelihood of an action potential in the postsynaptic cell.^[7] This process facilitates signal propagation in neural circuits, with the primary neurotransmitter in most vertebrate central nervous system excitatory synapses being glutamate.^[4] Structurally, an excitatory synapse comprises a presynaptic terminal—typically an axonal bouton filled with synaptic vesicles—a synaptic cleft measuring 20–40 nm in width that separates the pre- and postsynaptic membranes, and a postsynaptic density (PSD), an electron-dense protein scaffold approximately 30 nm thick that organizes receptors and signaling molecules.^[8]^[9] The synaptic vesicles, about 50 nm in diameter, store neurotransmitters for release.^[10] The functional hallmark of excitatory synapses is the production of an excitatory postsynaptic potential (EPSP), resulting from a net influx of positively charged ions such as Na⁺ and Ca²⁺ into the postsynaptic neuron, which shifts the membrane potential toward the threshold for action potential initiation.^[7] Transmission occurs in a quantal manner, with each vesicle releasing approximately 5,000 glutamate molecules upon fusion with the presynaptic membrane, ensuring discrete and reliable signaling.^[11] Excitatory synapses are evolutionarily conserved, appearing in nervous systems from invertebrates to mammals, underscoring their fundamental role in neural communication across animal phyla.^[12]

Comparison with Inhibitory Synapses

Excitatory and inhibitory synapses share fundamental structural and mechanistic elements, including the presynaptic release of neurotransmitters from vesicles in response to action potentials and the binding of these neurotransmitters to specific receptors on the postsynaptic membrane, which triggers ion channel opening. However, they differ markedly in the direction and nature of ion flow across the postsynaptic membrane: excitatory synapses typically facilitate cation influx (such as Na⁺ or Ca²⁺), depolarizing the postsynaptic neuron, while inhibitory synapses promote anion influx (Cl⁻) or cation efflux (K⁺), leading to hyperpolarization or stabilization of the membrane potential.^[1]^[13] Inhibitory synapses primarily utilize neurotransmitters like γ-aminobutyric acid (GABA) or glycine, which bind to ionotropic receptors such as GABA_A or glycine receptors, causing Cl⁻ influx that hyperpolarizes the postsynaptic neuron by shifting the membrane potential toward the Cl⁻ reversal potential (around -70 mV). Metabotropic GABA_B receptors, in contrast, activate G-protein-coupled pathways that open K⁺ channels, resulting in K⁺ efflux and further hyperpolarization. This contrasts with excitatory synapses, where glutamate or acetylcholine binding opens cation-permeable channels, generating depolarizing excitatory postsynaptic potentials (EPSPs).^[13]^[4] The interplay between excitatory and inhibitory synapses maintains balance in neural circuits, where excitatory inputs drive action potential generation and information propagation, while inhibitory inputs prevent overexcitation, ensuring network homeostasis and preventing conditions like seizures. In the cerebral cortex, this balance is reflected in an approximate 4:1 ratio of excitatory to inhibitory neurons, allowing excitatory drive to predominate under normal conditions while inhibition modulates timing and gain. Functionally, excitatory synapses promote temporal and spatial summation of EPSPs to reach the action potential threshold, facilitating signal integration, whereas inhibitory synapses generate inhibitory postsynaptic potentials (IPSPs) that either subtract from EPSPs through hyperpolarization or shunt excitatory currents by increasing membrane conductance without significant voltage change.^[14]^[15]^[16] Representative examples illustrate these roles: excitatory synapses often form between pyramidal neurons in cortical layers, using glutamate to propagate signals across networks, whereas inhibitory synapses typically connect GABAergic interneurons to pyramidal cells or other interneurons, providing local feedback inhibition to refine circuit dynamics.^[16]^[17]

Synapse Types

Chemical Synapses

Chemical synapses are specialized junctions between neurons that facilitate communication through the release of diffusible chemical messengers, termed neurotransmitters, which traverse a narrow synaptic cleft (approximately 20-40 nm wide) to bind specific receptors on the postsynaptic membrane. This process contrasts with electrical synapses, where direct ion flow occurs via gap junctions without chemical intermediaries. The synaptic cleft physically separates the presynaptic and postsynaptic membranes, ensuring unidirectional signal transmission from the presynaptic neuron to the postsynaptic one.^[18] Central to the structure of chemical synapses is the presynaptic terminal, which houses synaptic vesicles—small, spherical, membrane-bound organelles with diameters of 30-50 nm that store neurotransmitters. These vesicles cluster at the active zone, a protein-dense region of the presynaptic membrane that orchestrates docking and fusion. Key proteins in this zone include SNARE complexes (e.g., syntaxin-1, SNAP-25, and synaptobrevin/VAMP), which mediate vesicle docking and prime them for exocytosis upon calcium influx triggered by an arriving action potential. Following fusion and neurotransmitter release, synaptic vesicles are recycled through clathrin-mediated endocytosis, allowing reuse and maintaining synaptic efficacy over repeated activity. The postsynaptic density, opposite the active zone, consists of receptor proteins and scaffolding molecules that anchor and organize receptors for efficient signaling.^[19]^[20]^[21] Chemical synapses predominate in the vertebrate central nervous system (CNS), forming the vast majority of neuronal connections and serving as the primary mechanism for excitatory signaling. This prevalence enables intricate neural processing, as chemical transmission supports modulation of signal strength and duration. Unlike the rapid but rigid electrical coupling, chemical synapses are essential for synaptic plasticity, allowing adaptive changes in connectivity that underpin learning and memory.^[18]^[22] The advantages of chemical synapses lie in their capacity for signal amplification, where a single presynaptic action potential can release thousands of neurotransmitter molecules, generating a robust postsynaptic response. They also permit integration of multiple inputs at the postsynaptic site, summing excitatory signals spatially and temporally for decision-making in neural circuits. Furthermore, the diversity of postsynaptic receptors confers specificity, enabling tailored excitatory outcomes based on receptor subtype and localization. These features make chemical synapses ideal for the complex, modifiable excitatory networks in the vertebrate brain.^[23] The foundational description of chemical synapses emerged from the histological observations of Santiago Ramón y Cajal, who in 1897 characterized them poetically as "protoplasmic kisses," emphasizing the intimate yet distinct contact between neuronal processes. This insight, derived from Golgi-stained preparations, laid the groundwork for understanding synapses as discrete units of communication.^[24]

Electrical Synapses

Electrical synapses, also known as gap junctions, facilitate direct electrical communication between neurons by allowing the passive flow of ions and small molecules through specialized intercellular channels. These channels are formed by connexin proteins, where each hemichannel (connexon) consists of six connexin subunits, and two apposed hemichannels from adjacent cells align to create a complete gap junction with a pore diameter of approximately 1.5 nm, permitting bidirectional passage of molecules smaller than 1 kDa, such as ions and second messengers.^[25]^[26]^[27] In the context of excitatory transmission, electrical synapses promote synchronization of neuronal activity by enabling rapid, bidirectional current spread that can amplify and coordinate depolarizing signals across coupled cells. For instance, in retinal horizontal cells, these synapses support lateral inhibition and signal integration, enhancing collective responses to visual stimuli. Unlike chemical synapses, which predominate in the mammalian brain, electrical synapses lack a synaptic delay, allowing near-instantaneous transmission, but they offer limited modifiability and can propagate both excitatory and inhibitory signals equally, reducing specificity in signal processing.^[28]^[22]^[29] Electrical synapses are relatively rare in the adult mammalian central nervous system, comprising only a small fraction of total synapses and are more prevalent in invertebrates, non-mammalian vertebrates, and during early mammalian development when they aid in circuit formation. Their conductance is regulated by voltage-dependent gating, where transjunctional voltage differences can close channels, and by intracellular calcium levels, as elevated Ca²⁺ concentrations (above 10⁻⁴ M) trigger channel closure to prevent excessive ion leakage. A notable example of their role in excitatory synchronization occurs in the Mauthner cells of fish, where electrical synapses contribute to rapid escape responses by facilitating fast, bidirectional current flow that coordinates bilateral motor output during startle reflexes.^[30]^[31]^[32]^[33]

Synaptic Transmission

Presynaptic Mechanisms

Upon arrival of an action potential at the presynaptic terminal of an excitatory synapse, the depolarization opens voltage-gated calcium channels, primarily N-type (CaV2.2) and P/Q-type (CaV2.1), allowing Ca²⁺ influx that triggers neurotransmitter release.^[34]^[35] These channels are localized at the active zone, ensuring rapid and localized Ca²⁺ elevation within microseconds of depolarization.^[36] The influxed Ca²⁺ binds to synaptotagmin, a calcium sensor on the synaptic vesicle membrane, which then interacts with the SNARE complex—comprising syntaxin and SNAP-25 on the plasma membrane and VAMP (synaptobrevin) on the vesicle—to promote rapid vesicle fusion with the presynaptic membrane.^[37]^[38] This Ca²⁺-synaptotagmin-SNARE mechanism ensures synchronous release with high fidelity, with vesicle release probability typically ranging from 0.1 to 0.5 per action potential at central excitatory synapses.^[39] Synaptic vesicles are organized into distinct pools, with the readily releasable pool (RRP) consisting of approximately 5–10 docked and primed vesicles per active zone that can be rapidly exocytosed upon Ca²⁺ elevation.^[40] After release, vesicle recycling occurs primarily through clathrin-mediated endocytosis, which retrieves membrane and reforms vesicles to replenish the RRP and sustain transmission during repetitive activity.^[41]^[42] Quantal release is evident in the occurrence of miniature excitatory postsynaptic potentials (mEPSPs), which represent spontaneous fusion of single vesicles at rest and have a typical amplitude of about 0.5 mV in central neurons.^[43] These events underscore the discrete, packet-based nature of neurotransmitter release from the presynaptic terminal. Presynaptic release is modulated by autoreceptors on the terminal, which detect released neurotransmitter to provide feedback inhibition, and by retrograde signaling, such as endocannabinoids released from the postsynaptic neuron that act on presynaptic cannabinoid receptors to depress further release.^[44]^[45] These mechanisms allow dynamic adjustment of release probability in response to synaptic activity.^[46]

Postsynaptic Mechanisms

Following presynaptic release, excitatory neurotransmitters such as glutamate or acetylcholine diffuse rapidly across the synaptic cleft, a narrow extracellular space approximately 20-40 nm wide, reaching the postsynaptic membrane in approximately 1 μs.^[47] This diffusion is driven by concentration gradients established by vesicular release, allowing the neurotransmitter to bind to extracellular domains of postsynaptic receptors with high specificity and speed. Upon binding, the neurotransmitter concentration in the cleft transiently peaks at high levels, around 1 mM for glutamate during intense synaptic activity, creating a steep gradient that facilitates efficient receptor activation.^[48] These elevated concentrations decay rapidly, often within milliseconds, primarily through reuptake mechanisms mediated by transporters such as excitatory amino acid transporters (EAATs), which are enriched on astrocytic processes near the synapse and actively clear glutamate to prevent spillover and maintain signal fidelity.^[49] For acetylcholine, enzymatic degradation by acetylcholinesterase in the cleft similarly ensures quick termination, hydrolyzing the neurotransmitter into inactive components like choline and acetate.^[18] Postsynaptic receptors are precisely localized and clustered within the postsynaptic density (PSD), a protein-rich specialization beneath the membrane that organizes synaptic signaling components. Scaffold proteins like PSD-95 play a central role in this anchoring, binding to the intracellular tails of receptors via PDZ domains to stabilize their position and enhance synaptic efficacy at excitatory glutamatergic synapses.^[50] This clustering, involving interactions with cytoskeletal elements and other PSD constituents, ensures that receptors are optimally positioned to detect arriving neurotransmitters without significant lateral diffusion.^[51] The initial step of postsynaptic signaling occurs when neurotransmitter binding to the receptor's extracellular ligand-binding domain induces a conformational change in the receptor protein, transitioning it from a resting to an activated state.^[52] This structural rearrangement alters the receptor's pore or coupling properties, setting the stage for downstream effects while the process remains confined to the immediate postsynaptic locale. Overall termination of the signal relies on the combined actions of diffusion away from the cleft, reuptake into presynaptic terminals or glia, and enzymatic breakdown where applicable, restoring baseline conditions for subsequent transmissions.^[18]

Excitatory Neurotransmitters and Receptors

Glutamate and Its Receptors

Glutamate serves as the primary excitatory neurotransmitter in the central nervous system (CNS), mediating the majority of excitatory synaptic transmission. It is the most abundant neurotransmitter in the brain, accounting for approximately 90% of all synapses.^[53] Synthesized primarily from glutamine, glutamate is produced in presynaptic neurons through the action of the enzyme phosphate-activated glutaminase, which converts glutamine to glutamate.^[54] This process is part of the glutamate-glutamine cycle, where astrocytes release glutamine to replenish neuronal stores after glutamate release and uptake. Once synthesized, glutamate is loaded into synaptic vesicles by vesicular glutamate transporters (VGLUT1–3), which use a proton electrochemical gradient to sequester it for release.^[53] Glutamate is particularly dominant in the forebrain and spinal cord, where it underlies learning, memory, and motor control.^[55] Glutamate exerts its effects through two main classes of receptors: ionotropic and metabotropic. Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate fast synaptic transmission. The AMPA receptors (AMPARs), composed of GluA1–4 subunits, are responsible for the rapid depolarization of postsynaptic neurons via sodium influx, with activation kinetics around 5 ms.^[56] NMDA receptors (NMDARs), formed by GluN1 and GluN2 (A–D) or GluN3 subunits, are unique due to their voltage-dependent magnesium block and high calcium permeability, enabling slower responses (~100 ms) critical for synaptic plasticity.^[57] Kainate receptors (KARs), built from GluK1–5 subunits, play modulatory roles in synaptic tuning and presynaptic regulation rather than primary fast excitation.^[56] Recent cryo-electron microscopy (cryo-EM) structures from the 2020s have revealed subunit diversity and conformational dynamics, such as the tetrameric assembly of AMPARs and ligand-binding mechanisms in NMDARs, enhancing understanding of their gating properties.^[58] Metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors that modulate slower, longer-lasting responses. Group I mGluRs (mGluR1 and mGluR5) couple to Gq proteins, activating phospholipase C and the IP3 pathway to increase intracellular calcium and enhance neuronal excitability.^[59] In contrast, Groups II (mGluR2/3) and III (mGluR4/6/7/8) mGluRs link to Gi/o proteins, inhibiting adenylyl cyclase and reducing presynaptic glutamate release to fine-tune excitability.^[59] These receptors are widely distributed in the CNS, with Group I predominantly postsynaptic and Groups II/III often presynaptic. Cryo-EM studies in the 2020s have further elucidated their dimeric structures and allosteric modulation sites.^[60]

Acetylcholine and Its Receptors

Acetylcholine (ACh) serves as an excitatory neurotransmitter primarily at the neuromuscular junction and in select central nervous system (CNS) circuits, such as those originating from the basal forebrain, where it modulates cognitive functions including attention and memory.^[61] It is synthesized in cholinergic neurons through the enzymatic action of choline acetyltransferase (ChAT), which catalyzes the transfer of an acetyl group from acetyl-coenzyme A (acetyl-CoA) to choline, yielding ACh.^[62] This synthesis occurs in the cytoplasm of presynaptic terminals, ensuring a ready supply for vesicular packaging and release.^[63] ACh exerts its excitatory effects via two main classes of receptors: ionotropic nicotinic acetylcholine receptors (nAChRs) and metabotropic muscarinic acetylcholine receptors (mAChRs). Nicotinic receptors are pentameric ligand-gated ion channels composed of α and β subunits, permeable to sodium (Na⁺) and calcium (Ca²⁺) ions, which upon ACh binding allow rapid influx of these cations, depolarizing the postsynaptic membrane with kinetics on the order of 10 milliseconds.^[64] In the brain, the α4β2 subtype predominates, contributing to fast excitatory transmission in regions like the hippocampus and cortex.^[65] In contrast, muscarinic receptors are G-protein-coupled receptors that mediate slower, modulatory excitatory signaling; subtypes M1 and M3, coupled to Gq proteins, activate phospholipase C to produce inositol 1,4,5-trisphosphate (IP3) and diacylglycerol, leading to intracellular Ca²⁺ release and subsequent neuronal excitation.^[61]^[66] Following synthesis, ACh is transported into synaptic vesicles by the vesicular acetylcholine transporter (VAChT), an antiporter that exchanges cytoplasmic ACh for protons in the vesicle interior, concentrating the neurotransmitter for subsequent exocytotic release.^[67] To terminate signaling, acetylcholinesterase (AChE), a serine hydrolase enzyme, rapidly hydrolyzes ACh in the synaptic cleft into choline and acetate, with each AChE molecule capable of degrading approximately 25,000 ACh molecules per second, thereby preventing prolonged excitation.^[68] In specific neural circuits, ACh drives excitatory transmission in autonomic ganglia, where nicotinic receptors facilitate signal relay, and in the hippocampus, where basal forebrain projections enhance synaptic plasticity and oscillatory activity.^[69]^[70] Recent studies have further linked cholinergic signaling to attention circuits; for instance, basal forebrain ACh input adaptively allocates attention to enhance sensory discrimination, while it modulates theta oscillations across the hippocampal formation to support memory-related processes.^[71]^[72]

Other Excitatory Neurotransmitters

Catecholamines, including dopamine and norepinephrine, function as excitatory neurotransmitters in specific neural pathways, such as reward circuits and arousal systems. Dopamine exerts excitatory effects primarily through D1-like receptors, which couple to Gs proteins to stimulate adenylate cyclase and increase cyclic AMP (cAMP) levels, thereby enhancing neuronal excitability in prefrontal cortical pyramidal neurons and striatal direct pathway medium spiny neurons.^[73]^[74]^[75] Norepinephrine similarly promotes excitatory synaptic transmission, for instance by facilitating glutamate release at olfactory bulb synapses and suppressing inhibitory inputs in the amygdala to enable long-term potentiation.^[76]^[77] These catecholamines are biosynthesized from the amino acid tyrosine via sequential enzymatic steps, beginning with hydroxylation by tyrosine hydroxylase to form L-DOPA.^[78] Serotonin (5-hydroxytryptamine, 5-HT) acts as an excitatory neurotransmitter through certain receptor subtypes, notably 5-HT2 and 5-HT3 receptors, which mediate depolarization in cortical and other neurons. The 5-HT2 receptors couple to Gq proteins to activate phospholipase C and produce inositol trisphosphate (IP3), leading to calcium mobilization and enhanced excitability, while 5-HT3 receptors function as ligand-gated ion channels permeable to cations, directly causing rapid depolarization and increased neurotransmitter release.^[79]^[80] These actions contribute to serotonin's roles in regulating mood and arousal, with excitatory signaling promoting vigilance and emotional processing.^[81] Histamine serves as an excitatory neurotransmitter particularly in hypothalamic circuits, where it activates H1 receptors coupled to Gq proteins, triggering the IP3 signaling pathway to increase intracellular calcium and neuronal excitability.^[82] Synthesized from the amino acid histidine by the enzyme histidine decarboxylase, histamine plays a key role in promoting wakefulness through projections from tuberomammillary nucleus neurons.^[83]^[84] These neurotransmitters share common characteristics as primarily neuromodulatory agents, exerting diffuse and context-dependent effects rather than fast point-to-point signaling, and they occur in lower abundance compared to glutamate, with fewer synthesizing neurons in the brain.^[85] Catecholamines, along with serotonin and histamine, are packaged into synaptic vesicles via vesicular monoamine transporters (VMATs) for catecholamines and similar mechanisms for the others.^[86] Recent research since 2020 has highlighted aspartate's emerging role as a co-transmitter with glutamate at certain excitatory synapses, where it is released alongside glutamate to modulate NMDA receptor activation and synaptic plasticity, as evidenced by advanced biosensors detecting dynamic aspartate fluctuations in neural tissue.^[87]^[88]

Postsynaptic Responses

Ionotropic Responses

In ionotropic responses at excitatory synapses, the binding of neurotransmitters such as glutamate to ligand-gated ion channels in the postsynaptic membrane rapidly opens cation-selective pores that are primarily permeable to sodium (Na⁺) and potassium (K⁺) ions. This influx of Na⁺, driven by its electrochemical gradient, causes a fast depolarization known as the excitatory postsynaptic potential (EPSP), with a typical rise time of 0.5-2 milliseconds.^[89] The rapid kinetics of this response enable precise temporal coding in neural circuits, contributing to spike timing-dependent plasticity.^[90] The amplitude of a single quantum of neurotransmitter release, corresponding to a miniature EPSP (mEPSP), is typically 0.1–0.5 mV at the soma, varying widely (0.03–1 mV or more) by synapse location, neuron type, and recording conditions in central excitatory synapses.^[91] To initiate an action potential, multiple EPSPs must summate temporally (from repeated presynaptic activity) or spatially (from concurrent inputs at different synapses) to reach a depolarization threshold of approximately 15 mV from the resting potential of -70 mV.^[92] This summation process amplifies weak individual signals into a coherent excitatory drive, ensuring efficient information propagation without constant high-energy demand.^[93] Key examples of ionotropic receptors mediating these responses include α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors for fast glutamatergic transmission in most central nervous system excitatory synapses, where they underlie the initial phase of EPSPs.^[94] In cholinergic systems, nicotinic acetylcholine receptors serve a similar role, generating rapid depolarizations at select CNS excitatory synapses, such as those in the hippocampus.^[95] These receptors facilitate quick excitatory signaling essential for attention and learning processes.^[96] Prolonged exposure to neurotransmitter leads to receptor desensitization, where ion channels enter an inactivated state despite ligand binding, thereby preventing synaptic overload and maintaining response fidelity during sustained activity.^[97] For AMPA receptors, this involves conformational changes that close the channel pore, with recovery times on the order of milliseconds to seconds.^[98] Desensitization thus acts as a protective mechanism, limiting excessive Na⁺ influx and potential cellular damage.^[99] The energetics of these responses are governed by the electrochemical gradients across the postsynaptic membrane, particularly the Na⁺ equilibrium potential (E_Na) of approximately +55 mV, which provides the driving force for net cation influx and depolarization.^[100] K⁺ permeability contributes to the reversal potential near 0 mV for many AMPA receptors, ensuring the EPSP peaks below E_Na and decays promptly. This gradient—maintained by the Na⁺/K⁺-ATPase pump—sustains the efficacy of repeated ionotropic activations without rapid exhaustion.^[101]

Metabotropic Responses

Metabotropic responses in excitatory synapses arise from the activation of G-protein-coupled receptors (GPCRs) by neurotransmitters such as glutamate, leading to indirect modulation of postsynaptic signaling through intracellular cascades. Upon ligand binding, these receptors catalyze GDP-GTP exchange on associated G proteins, dissociating the Gα subunit to activate downstream effectors.^[59] In excitatory contexts, group I metabotropic glutamate receptors (mGluR1 and mGluR5) predominantly couple to Gq/11 proteins, stimulating phospholipase Cβ to hydrolyze phosphatidylinositol 4,5-bisphosphate into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).^[102] IP3 triggers calcium release from intracellular stores, while DAG activates protein kinase C (PKC), both of which alter ion channel function and neuronal excitability over extended periods.^[59] Excitatory signaling pathways via these metabotropic receptors enhance postsynaptic depolarization and synaptic efficacy. Gq-coupled activation increases intracellular calcium, which can suppress potassium conductances (e.g., leak K⁺ channels), reducing hyperpolarizing currents and promoting membrane depolarization.^[103] In parallel, Gs-coupled metabotropic receptors, such as certain serotonin 5-HT receptors, elevate cyclic AMP (cAMP) levels through adenylyl cyclase stimulation, activating protein kinase A (PKA) to phosphorylate and close K⁺ channels, further facilitating excitation.^[104] These mechanisms contrast with the rapid ionotropic phase by providing modulatory amplification rather than direct conductance changes.^[105] The duration of metabotropic responses typically spans from hundreds of milliseconds to several minutes, enabling temporal integration of synaptic inputs and long-term modulation of excitability.^[104] This prolonged signaling enhances the efficacy of fast ionotropic responses, for example, by facilitating calcium-dependent processes that sustain depolarization or promote synaptic plasticity.^[105] Representative examples include mGluR1/5 activation, which potentiates NMDA receptor currents in hippocampal CA1 pyramidal neurons via PKC-mediated phosphorylation and calcium elevation, thereby amplifying excitatory transmission.^[106] Similarly, in serotonergic systems, 5-HT₂ receptor stimulation via Gq pathways boosts cortical excitability by closing K⁺ channels and enhancing glutamate release.^[102] Regulatory feedback mechanisms limit metabotropic signaling to prevent overstimulation. Desensitization occurs through β-arrestin recruitment to phosphorylated receptors, uncoupling G proteins and promoting internalization, which attenuates responses over time.^[107] Recent studies on biased agonism highlight how ligands can selectively favor G-protein or arrestin pathways, influencing desensitization and therapeutic targeting in excitatory disorders, as demonstrated in GPCR models from the 2010s.^[108]

Pathophysiology and Diseases

Excitotoxicity

Excitotoxicity refers to a pathological process in which excessive activation of excitatory synapses, primarily by glutamate, leads to neuronal death through overload of ionotropic receptors and subsequent intracellular disruptions. This phenomenon arises when extracellular glutamate concentrations rise beyond physiological levels, causing prolonged depolarization and influx of calcium ions (Ca²⁺) via N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, ultimately triggering cell demise via necrosis or apoptosis.^[109] The term excitotoxicity was coined by John W. Olney based on his seminal observations in 1969, where systemic administration of monosodium glutamate to newborn mice induced selective neuronal lesions in brain regions such as the hypothalamus and arcuate nucleus, highlighting glutamate's dual role as a neurotransmitter and potential neurotoxin. This discovery laid the foundation for understanding how excitatory signaling can turn deleterious, particularly in models of acute brain injury like stroke, where excitotoxicity contributes significantly to infarct expansion.^[110]^[111] Common triggers include cerebral ischemia and traumatic brain injury, which impair energy metabolism and glutamate uptake, leading to accumulation of extracellular glutamate and excessive Ca²⁺ entry through NMDA receptors. Mitochondrial dysfunction further exacerbates this by failing to buffer Ca²⁺, promoting the production of reactive oxygen species (ROS) such as superoxide and peroxynitrite, which damage lipids, proteins, and DNA. The downstream cascade involves activation of Ca²⁺-dependent proteases like calpains, which degrade cytoskeletal elements and initiate apoptotic pathways, culminating in either necrotic swelling or programmed cell death depending on the severity of the insult.^[109]^[112] A critical threshold distinguishes normal excitatory postsynaptic potentials (EPSPs) from pathological ones: physiological synaptic glutamate peaks transiently at around 1 mM in the cleft for milliseconds, generating EPSPs of 0.5–5 mV without harm, whereas sustained elevations above 10–100 μM extracellularly provoke excitotoxicity by overwhelming clearance mechanisms. Recent research emphasizes the role of glial buffering failure in crossing this threshold; astrocytes normally uptake ~90% of released glutamate via transporters like GLT-1, but under energy-deprived conditions such as ischemia, this uptake fails, leading to prolonged glutamate exposure and amplified excitotoxic damage.^[113]^[114]

Neurodegenerative Disorders

Dysfunction at excitatory synapses, particularly involving dysregulated glutamate signaling and excitotoxicity, plays a central role in the pathogenesis of several neurodegenerative disorders. In these conditions, alterations in neurotransmitter release, receptor activity, and synaptic clearance contribute to neuronal damage and progressive loss of synaptic integrity. While excitotoxicity mechanisms, such as excessive calcium influx through NMDA receptors, underlie many of these changes, their manifestation varies across diseases, leading to region-specific vulnerabilities and clinical symptoms.^[115] In Alzheimer's disease (AD), amyloid-β (Aβ) oligomers enhance NMDA receptor activity, promoting excitotoxic calcium entry and synaptic dysfunction early in the disease process. This potentiation of glutamate sensitivity and NMDA activation disrupts normal synaptic transmission and contributes to cognitive decline. Additionally, tau pathology, through hyperphosphorylated tau aggregates, impairs synaptic vesicle release and mobility, leading to presynaptic dysfunction and loss of excitatory synapses in hippocampal and cortical regions. These combined effects exacerbate neuronal vulnerability and correlate with memory impairment.^[116]^[117] Parkinson's disease (PD) involves dopamine loss in the substantia nigra, which disrupts the excitatory-inhibitory balance within basal ganglia circuits. This imbalance arises as reduced dopaminergic modulation favors excessive glutamatergic excitation in the indirect pathway, leading to overactivity in the subthalamic nucleus and downstream motor impairments such as bradykinesia and rigidity. Synaptic alterations in striatal medium spiny neurons further amplify this dysregulation, contributing to the motor and non-motor symptoms of PD.^[118]^[119] Amyotrophic lateral sclerosis (ALS) features increased glutamate release associated with mutant superoxide dismutase 1 (SOD1), heightening excitotoxic stress on motoneurons. In SOD1 G93A mouse models, this elevated release overwhelms astrocytic uptake, causing chronic activation of AMPA and NMDA receptors and selective vulnerability of spinal motoneurons to degeneration. The resulting synaptic failure propagates to muscle atrophy and progressive paralysis, highlighting the role of excitatory imbalance in ALS pathogenesis.^[120] In Huntington's disease (HD), mutant huntingtin protein impairs EAAT2 (GLT-1) expression in astrocytes, reducing glutamate uptake and prolonging excitatory signaling at synapses. This dysfunction leads to elevated extracellular glutamate levels, fostering excitotoxicity in striatal medium spiny neurons and contributing to chorea and cognitive deficits. Mutant huntingtin's effects on glial support thus amplify synaptic vulnerability in HD.^[121] Emerging research as of 2025 links failures in synaptic pruning, mediated by microglial complement pathways, to early stages of neurodegenerative diseases like AD. Dysregulated pruning of excitatory synapses, driven by aberrant C1q and C3 activation, results in excessive synapse loss before overt plaque or tangle formation, potentially serving as a preclinical biomarker and therapeutic target.^[122]^[123]

References

[1]
Excitatory and Inhibitory Postsynaptic Potentials - NCBI - NIH
PSPs are called excitatory (or EPSPs) if they increase the likelihood of a postsynaptic action potential occurring, and inhibitory (or IPSPs) if they decrease ...
[2]
Biochemistry, Glutamate - StatPearls - NCBI Bookshelf - NIH
Glutamate is the principal excitatory neurotransmitter of the central nervous system and the most abundant neurotransmitter in the brain.
[3]
Action potentials and synapses - Queensland Brain Institute
These are respectively termed excitatory and inhibitory inputs, as they promote or inhibit the generation of action potentials (the reason some inputs are ...
[4]
Amino Acid Neurotransmitters (Section 1, Chapter 13) Neuroscience ...
Because glutamate is the major excitatory transmitter in the human brain, derangements in glutamate metabolism or receptor activation have been implicated ...Missing: primary | Show results with:primary
[5]
Overview of the Glutamatergic System - Glutamate-Related ... - NCBI
Glutamate is the major excitatory neurotransmitter in the nervous system. Glutamate pathways are linked to many other neurotransmitter pathways.
[6]
Editorial: Latest Advances on Excitatory Synapse Biology - Frontiers
In the central nervous system, excitatory synapses represent the primary means of information processing by local circuits and communication between brain ...Missing: definition | Show results with:definition
[7]
Excitatory Synapse - an overview | ScienceDirect Topics
Excitatory synapses are defined as synaptic connections that facilitate the transmission of signals between neurons by allowing the influx of positively ...
[8]
Synaptic Cleft - an overview | ScienceDirect Topics
The width of the synaptic cleft is 20–30 nm at synapses between neurons in the central nervous system and about 50 nm at the neuromuscular junction.
[9]
The Postsynaptic Organization of Synapses - PMC - PubMed Central
The postsynaptic side receives neurotransmitters, with receptors and a protein network. Excitatory synapses have a postsynaptic density (PSD) on dendritic ...Missing: width | Show results with:width
[10]
Presynaptic Terminal - an overview | ScienceDirect Topics
The presynaptic terminal contains densely packed synaptic vesicles (SVs), typically about 50 nm in diameter, clustered around electron-dense active zones (AZs), ...
[11]
A mean-field model of glutamate and GABA synaptic dynamics for ...
Feb 1, 2023 · Assuming 5000 Glu molecules per vesicle ... Delayed clearance of transmitter and the role of glutamate transporters at synapses with multiple ...
[12]
Common Mechanisms of Synaptic Plasticity in Vertebrates and ...
Jan 12, 2010 · General model for learning-related enhancement of excitatory glutamatergic synapses. This model is based on recent data from studies of synaptic ...
[13]
GABA and Glycine Receptors - Neuroscience - NCBI Bookshelf - NIH
A second mechanism for GABAB-mediated inhibition is by blocking Ca2+ channels, which tends to hyperpolarize postsynaptic cells. Unlike most metabotropic ...
[14]
An 80/20 cortical balance stabilizes information-rich dynamics
Sep 24, 2025 · The cortex maintains a remarkably consistent 4:1 ratio between excitatory and inhibitory neurons, yet the computational advantages of such ...
[15]
Summation of Synaptic Potentials - Neuroscience - NCBI Bookshelf
The summation of EPSPs and IPSPs by a postsynaptic neuron permits a neuron to integrate the electrical information provided by all the inhibitory and ...Missing: functional shunts subtracts
[16]
Proximity of excitatory and inhibitory axon terminals adjacent ... - PNAS
Jun 16, 2009 · Many studies have shown that pyramidal neurons are glutamatergic and that they exert a fundamental excitatory function in cortical circuits (3).
[17]
Pyramidal cell-interneuron circuit architecture and dynamics in ...
Total number and ratio of excitatory and inhibitory synapses converging onto single interneurons of different types in the CA1 area of the rat hippocampus.
[18]
Physiology, Synapse - StatPearls - NCBI Bookshelf
Mar 27, 2023 · Axodendritic is a connection formed between the axon of 1 neuron and the dendrite of another. These tend to be excitatory synapses.
[19]
Structure and topography of the synaptic V-ATPase–synaptophysin ...
Jun 5, 2024 · Synaptic vesicles are small organelles with an average diameter of approximately 40 nm and a specific composition of proteins and lipids.
[20]
SNARE Regulatory Proteins in Synaptic Vesicle Fusion and Recycling
SNAREs are a large protein family characterized by a ∼70 amino acid α-helical heptad repeat known as the SNARE motif. Based on their primary subcellular ...
[21]
Synaptic vesicle recycling: steps and principles - PMC
SCRAPPER-dependent ubiquitination of active zone protein RIM1 regulates synaptic vesicle release. ... The SNARE proteins SNAP25 and synaptobrevin are involved in ...
[22]
Electrical Synapses - Neuroscience - NCBI Bookshelf - NIH
Electrical synapses use gap junctions for direct, fast, bidirectional ionic current flow between neurons, allowing molecules to diffuse.
[23]
Chemical Synapse - an overview | ScienceDirect Topics
The chemical synapse allows both the complex integration ... synapses, but it provides the advantage of directionality and amplification of signal transmission.
[24]
on the cell biology of synapses, behaviors, and networks in science
Nov 1, 2016 · Synapses, which are points of cellular communication between neurons, were first described by Santiago Ramón y Cajal as “protoplasmic kisses ...
[25]
Electrical synapses--gap junctions in the brain - PubMed
Connexin gap junction channels enable the intercellular, bidirectional transport of ions, metabolites, second messengers and other molecules smaller than 1 kD.
[26]
Electrical synapses: structure, locations, diagram | Kenhub
Nov 26, 2024 · Connexins are transmembrane ion channel proteins. One connexon comprises six connexins and a gap junction channel consists of twelve connexins.
[27]
The Permeability of Gap Junction Channels to Probes of Different ...
Estimates based on size cutoffs for permeants suggest that the effective pore diameter varies over a range of 8–16 Å, depending on the connexin isoform (Beblo ...
[28]
Electrical synapses convey orientation selectivity in the mouse retina
Dec 11, 2017 · Electrical synapses are most commonly present in dendrites and often aid in lateral signal spread and synchrony among functionally similar cells ...
[29]
Electrical Synapse - an overview | ScienceDirect Topics
The electrical synapse (also called Gap-junction) is a channel formed of proteins. Electrical synapses form a minority of all synapses and are enriched in ...
[30]
Electrical synapses in mammalian CNS: past eras, present focus ...
Electrical synapses, formed by gap junctions between neurons, have been studied extensively in the CNS of non-mammalian vertebrates beginning in the mid-20th ...
[31]
ELECTRICAL SYNAPSES IN THE MAMMALIAN BRAIN
Jul 21, 2004 · Many neurons in the mammalian central nervous system communicate through electrical synapses, defined here as gap junction–mediated connections.
[32]
Calcium Role in Gap Junction Channel Gating - MDPI
Sep 10, 2024 · The chemical gating of gap junction channels is mediated by cytosolic calcium (Ca2+i) at concentrations ([Ca2+]i) ranging from high ...
[33]
Connexin35 Mediates Electrical Transmission at Mixed Synapses ...
Auditory afferents terminating as “large myelinated club endings” on goldfish Mauthner cells are identifiable “mixed” (electrical and chemical) synaptic ...
[34]
Functions of Presynaptic Voltage-gated Calcium Channels - PMC
For most synapses, CaV2.1 (P/Q)- and CaV2.2 (N)-type channels are involved in varying proportions in synaptic transmission, depending on the synapse in question ...
[35]
Presynaptic Calcium Channels - MDPI
P/Q-type and N-type Ca2+ currents initiate neurotransmitter release at most fast synapses [1,8,9]. The Ca2+ channels are composed of four or five distinct ...
[36]
Diverse organization of voltage-gated calcium channels ... - Frontiers
Dec 4, 2022 · This review focuses on recent progress in our understanding of the organization of CaV channels at the presynaptic active zone, their underlying molecular ...
[37]
Dependent Synaptotagmin Binding to SNAP-25 Is Essential for Ca 2+
These results indicate that the Ca2+-dependent interaction of synaptotagmin with SNAP-25 is essential for the Ca2+-dependent triggering of membrane fusion.
[38]
SNARE Complex Formation Is Triggered by Ca2+ and Drives ...
The data suggest that Ca 2+ triggers S25-C binding to a low-affinity site, initiating trans-complex formation. Pairing of SNARE proteins on apposing membranes ...
[39]
Different priming states of synaptic vesicles underlie distinct release ...
Dec 21, 2022 · Article. Different priming states of synaptic vesicles underlie distinct release probabilities at hippocampal excitatory synapses.Missing: cleft | Show results with:cleft
[40]
Systematic Heterogeneity of Fractional Vesicle Pool Sizes and ...
The readily releasable pool (RRP) of 5–10 vesicles is already docked to the active zone and primed for fusion. The RRP can be released immediately upon a rapid ...
[41]
Article Clathrin-Mediated Endocytosis Is the Dominant Mechanism of ...
Sep 21, 2006 · These results indicate that clathrin-mediated endocytosis is the major, if not exclusive, mechanism of vesicle retrieval after physiological stimuli.
[42]
Clathrin-mediated endocytosis at the synaptic terminal
Most synaptic terminals in the brain contain no more than 100–200 vesicles, so the maintenance of communication depends on vesicles being recycled from the ...
[43]
Mechanisms of Neurotransmitter Release (Section 1, Chapter 5 ...
Katz noticed that the amplitude of the smallest EPP that could be evoked was the same amplitude (0.5 mV) as the amplitude of the MEPP. Based on these results ...Missing: mEPSPs | Show results with:mEPSPs
[44]
Presynaptic modulation by endocannabinoids - PubMed - NIH
This retrograde endocannabinoid modulation has been implicated in short-term synaptic depression, including suppression of excitatory or inhibitory transmission ...
[45]
Endocannabinoid Signaling and Synaptic Function
Oct 4, 2012 · Retrograde signaling is the principal mode by which endocannabinoids mediate short- and long-term forms of plasticity at both excitatory and ...
[46]
Endocannabinoid-mediated retrograde modulation of synaptic ...
2-AG mediates retrograde signals at various types of synapses in the brain. 2-AG mediates short- and long-term depression at excitatory and inhibitory synapses.
[47]
Glutamate transporter EAAT2: regulation, function, and potential as ...
The concentration of released glutamate from the pre-synaptic terminal reaches approximately 1 mM, and is rapidly decreased by binding to glutamate transporters ...Missing: peak | Show results with:peak
[48]
The role of glutamate transporters in the pathophysiology of ... - Nature
Sep 21, 2017 · Excitatory amino acid transporters (EAATs) are responsible for the reuptake of glutamate, preventing non-physiological spillover from the ...
[49]
Excitation Control: Balancing PSD-95 Function at the Synapse - PMC
A major scaffolding molecule localized at the PSD of excitatory glutamatergic synapses is the postsynaptic density protein PSD-95 (Figure 2). PSD-95 is a ...
[50]
PSD-95 Is Required to Sustain the Molecular Organization of the ...
Apr 27, 2011 · Overexpression of this construct recruits more AMPA receptors to synapses and increases synaptic transmission (El-Husseini et al., 2000; Futai ...Missing: transporters | Show results with:transporters
[51]
Synaptic Neurotransmitter-Gated Receptors - PMC - PubMed Central
The initial step in the activation pathway involves the binding of a neurotransmitter between neighboring subunit ECDs, coordinated by six binding loops, A–F.
[52]
Glutamate metabolism and recycling at the excitatory synapse in ...
Sep 15, 2021 · It is estimated that 90% of all synapses in the brain utilize glutamate, making this neurotransmitter the predominant mediator of excitatory ...
[53]
Glutamate - Neuroscience - NCBI Bookshelf - NIH
Glutamine is released by glial cells and, once within presynaptic terminals, is metabolized to glutamate by the mitochondrial enzyme glutaminase (Figure 6.9).
[54]
Overview of Glutamatergic Neurotransmission in the Nervous System
The following review will briefly outline the extremely complex physiology and ... Glutamate is the main excitatory neurotransmitter in the mammalian CNS.
[55]
Ionotropic and Metabotropic Receptors in Concert - PMC
In this review, by comparing both receptor families with a focus on their crosstalk, we argue for a more holistic understanding of neural glutamate signaling.
[56]
Glutamatergic Signaling in the Central Nervous System: Ionotropic ...
Jun 27, 2018 · In this review, by comparing both receptor families with a focus on their crosstalk, we argue for a more holistic understanding of neural glutamate signaling.
[57]
Cryo-EM structures of the ionotropic glutamate receptor GluD1 ...
Jan 10, 2020 · Here we report cryo-EM structures of the rat GluD1 receptor complexed with calcium and the ligand 7-chlorokynurenic acid (7-CKA), elucidating molecular ...Missing: 2020 | Show results with:2020
[58]
Metabotropic Glutamate Receptors: Physiology, Pharmacology, and ...
The metabotropic glutamate receptors (mGluRs) are family C G-protein-coupled receptors that participate in the modulation of synaptic transmission and neuronal ...
[59]
Structural and Biophysical Mechanisms of Class C G Protein ...
Based on cryo-EM structures, it was proposed that interactions between the CRD and extracellular loop 2 in mGluRs [20], or between the LBD-TMD linker and EL2 in ...
[60]
Physiology, Acetylcholine - StatPearls - NCBI Bookshelf
Muscarinic receptors M1, M3, and M5 all exert their functions through the stimulation of phospholipase C. When the α subunit of the G protein complex ...
[61]
Choline Acetyltransferase - an overview | ScienceDirect Topics
The enzymatic mechanism of ChAT involves the transfer of an acetyl group from acetyl-coenzyme A to choline, producing acetylcholine. 7 11 12. Acetyl-CoA is ...
[62]
Choline acetyltransferase: the structure, distribution and pathologic ...
ChAT is a single-strand globular protein. The enzyme is synthesized in the perikaryon of cholinergic neurones and transported to the nerve terminals.
[63]
Neuronal Nicotinic Acetylcholine Receptor Structure and Function ...
Nicotinic acetylcholine receptors (nAChRs) belong to the “Cys-loop” superfamily of ligand-gated ion channels that includes GABAA, glycine, and serotonin (5-HT3) ...
[64]
Mammalian Nicotinic Acetylcholine Receptors: From Structure to ...
This review provides a comprehensive overview of these findings and the more recent revelations of the impact that the rich diversity in function and expression ...
[65]
A New Era of Muscarinic Acetylcholine Receptor Modulators ... - MDPI
Muscarinic M1, M3, and M5 receptors mobilize phosphoinositides to produce inositol 1,4,5-trisphosphate and 1,2-diacylglycerol, leading to a rise in ...3. The Muscarinic Receptor · 5.1. M1 Muscarinic Agonists... · 7. M4 Subtype Selectivity
[66]
The Vesicular Acetylcholine Transporter Is Required for ...
The vesicular acetylcholine (ACh) transporter (VAChT) mediates ACh storage by synaptic vesicles. However, the VAChT-independent release of ACh is believed ...
[67]
Acetylcholinesterase Inhibitors: Pharmacology and Toxicology - PMC
AChE has a remarkably high specific catalytic activity, specially for a serine hydrolase - each molecule of AChE degrades about 25000 molecules of ACh per ...
[68]
Chapter 11: Acetylcholine Neurotransmission
ACh has excitatory actions at the neuromuscular junction, at autonomic ganglion, at certain glandular tissues and in the CNS. It has inhibitory actions at ...Missing: hippocampus | Show results with:hippocampus
[69]
The Cholinergic System Modulates Memory and Hippocampal ...
These data provide support for the view that basal forebrain ACh release may influence hippocampus and memory via slow inhibition of neuronal activity via ...
[70]
Basal forebrain cholinergic input mediates adaptive attention ...
Basal forebrain cholinergic input mediates adaptive attention allocation to enhance olfactory discrimination · Attention reduces behavioral uncertainty in an ...<|separator|>
[71]
Acetylcholine modulates the temporal dynamics of human theta ...
Aug 30, 2023 · Our results indicate that cholinergic circuits support memory by coordinating the temporal dynamics of theta oscillations across the hippocampal formation.
[72]
Stimulation of D1-type dopamine receptors enhances excitability in ...
Stimulation of D1-type dopamine receptors enhances excitability in prefrontal cortical pyramidal neurons in a state-dependent manner · Authors · Affiliation.
[73]
The Signaling and Pharmacology of the Dopamine D1 Receptor
While glutamatergic input provides the main excitatory stimulus that drives striatal neuron firing, dopamine signaling via D1R can act as a powerful modulator.
[74]
Dopamine D1–D5 Receptors in Brain Nuclei: Implications for ... - MDPI
The activation of D1 receptors heightens the excitability of dMSNs, instigating and facilitating the execution of motor functions. These receptors are also ...
[75]
Excitatory and inhibitory effects of noradrenaline on synaptic ...
It is concluded that at low concentrations, noradrenaline facilitates transmission at the LOT-superficial pyramidal cell synapse by increasing excitatory amino ...
[76]
Norepinephrine enables the induction of associative long ... - PNAS
We show that NE suppresses GABAergic inhibition of projection neurons in the lateral amygdala and enables the induction of LTP at thalamo-amygdala synapses.
[77]
Biosynthesis of Catecholamines - Basic Neurochemistry - NCBI - NIH
Tyrosine hydroxylase is the rate-limiting enzyme for the biosynthesis of catecholamines. Tyrosine hydroxylase (TH) is found in all cells that synthesize ...
[78]
5-HT2 and 5-HT3 receptors mediate two distinct depolarizing ...
5-HT produced a concentration-dependent depolarization in 88% of these neurons. Membrane input resistance (Rin), determined from the slope of current-voltage ...
[79]
Serotonin modulation of cortical neurons and networks - Frontiers
Apr 18, 2013 · 5-HT can also stimulate excitatory (5-HT2A and 5-HT3) and inhibitory (5-HT1A) receptors in GABA interneurons to modulate synaptic GABA inputs ...
[80]
Physiology, Serotonin - StatPearls - NCBI Bookshelf - NIH
Jul 30, 2023 · Serotonin, or 5-hydroxytryptamine (5-HT), is a neurotransmitter with an integral physiological role in the human body; it regulates various activities.
[81]
Histamine H1 Receptor - an overview | ScienceDirect Topics
IP3 mediates calcium release which leads to activation of numerous potential second messengers (cyclic guanosine monophosphate (cGMP) and cyclic adenosine ...
[82]
Histamine H1 receptor - Wikipedia
The H1 receptor is linked to an intracellular G-protein (Gq) that activates phospholipase C and the inositol triphosphate (IP3) signalling pathway.Missing: excitatory | Show results with:excitatory
[83]
HISTAMINE IN THE REGULATION OF WAKEFULNESS - PMC
Histamine in the brain is formed from the essential amino acid L-histidine (Fig 2). Histamine synthesis occurs in two steps: 1) neuronal uptake of L-histidine ...
[84]
Histamine in the regulation of wakefulness - ScienceDirect.com
Strong and consistent evidence exist to suggest that histamine, acting via H 1 and/or H 3 receptor has a pivotal role in the regulation of sleep-wakefulness.
[85]
Synaptic Vesicle Recycling Pathway Determines Neurotransmitter ...
May 22, 2019 · Signaling by neuromodulators such as monoamines differs in multiple ways from signaling by the classic neurotransmitters glutamate and GABA.
[86]
Vesicular Glutamate Transport Promotes Dopamine Storage and ...
Mar 11, 2010 · Vesicular glutamate transport (VGLUT2) promotes dopamine storage and glutamate corelease, and facilitates vesicle filling with dopamine.
[87]
Aspartate in the Brain: A Review - PMC - PubMed Central
Jun 12, 2025 · Here, we examine what is known about the various roles of aspartate in brain, its metabolism, transport and compartmentation, its role as a neurotransmitter.
[88]
An engineered biosensor enables dynamic aspartate ... - eLife
Results. Protein engineering. We observed that the glutamate sensor, iGluSnFR, binds both glutamate and aspartate, with higher affinity for the former (Marvin ...Protein Engineering · Asparagine Salvage Diverts... · Generation Of Got1/2 Double...
[89]
https://journals.physiology.org/doi/full/10.1152/jn.1999.82.3.1295
[90]
Differences in the Properties of Ionotropic Glutamate Synaptic ...
May 1, 1999 · EPSPs were evoked by a single- or high-frequency (50 Hz, 200 msec) extracellular stimulation dorsolateral to the SON.
[91]
Physiology, Action Potential - StatPearls - NCBI Bookshelf - NIH
In neurons, the rapid rise in potential, depolarization, is an all-or-nothing event that is initiated by the opening of sodium ion channels within the plasma ...
[92]
Mechanisms Underlying Developmental Speeding in AMPA-EPSC ...
At the excitatory synapse, speeding of the synaptic current decay contributes to faster rising EPSPs and reduced spike jitter, thereby increasing the temporal ...
[93]
AMPA receptors in the evolving synapse: structure, function, and ...
These include ionotropic receptors such as AMPA and NMDARs, which mediate fast excitatory transmission, as well as metabotropic glutamate receptors that ...
[94]
Nicotine Enhancement of Fast Excitatory Synaptic Transmission in ...
The behavioral and cognitive effects of nicotine suggest that nicotinic acetylcholine receptors (nAChRs) participate in central nervous system (CNS) function.
[95]
Nicotinic Acetylcholine Receptors at Glutamate Synapses Facilitate ...
Jun 29, 2005 · The results indicate that nAChRs may have various influences over excitatory events in the hippocampus. Ongoing nAChR activity likely modulates ...
[96]
Desensitization Properties of AMPA Receptors at the Cerebellar ...
Aug 1, 2007 · Native AMPA receptors (AMPARs) exhibit rapid and profound desensitization in the sustained presence of glutamate. Desensitization therefore ...
[97]
Desensitization dynamics of the AMPA receptor - ScienceDirect.com
Jun 1, 2023 · One example of the functional importance of transition kinetics is that AMPAR recovers from desensitization considerably faster than other ...
[98]
AMPA receptor desensitization mutation results in severe ... - PNAS
Desensitization involves a conformational change of the receptor complex that allows closure of the channel gate while glutamate remains bound to the receptor ( ...
[99]
Chapter 2. Ionic Mechanisms of Action Potentials
Na+ is critical for the action potential in nerve cells. As shown in ... Na+ equilibrium potential (+55 mV). The resting potential is -60 mV. Note ...
[100]
Physiology, Resting Potential - StatPearls - NCBI Bookshelf - NIH
In a normal cell, Na+ permeability is about 5% of the K+ permeability or even less, whereas the respective equilibrium potentials are +60 mV for sodium (ENa) ...
[101]
Metabotropic Receptors Modulate Synaptic Transmission - NCBI - NIH
Metabotropic receptor activation closes voltage-dependent, acetylcholine-sensitive and Ca2+-dependent K+ channels in certain neurons, leading to slow ...
[102]
Mechanisms underlying excitatory effects of group I metabotropic ...
To mediate fast excitatory transmission, glutamate activates postsynaptic ionotropic receptors. Glutamate also activates metabotropic receptors (mGluRs) ( ...
[103]
Metabotropic Receptor - an overview | ScienceDirect Topics
Responses mediated by metabotropic receptors are slower and longer-lasting than those of ionotropic receptors, typically persisting from seconds to minutes, ...<|separator|>
[104]
https://www.sciencedirect.com/topics/neuroscience/metabotropic-receptor
[105]
mGluR1-mediated potentiation of NMDA receptors involves a rise in ...
The present study tests the hypothesis that mGluR1-mediated potentiation of N-methyl-D-aspartate receptors (NMDARs) occurs via a phospholipase C (PLC)- ...
[106]
GPCR signaling via β-arrestin-dependent mechanisms - PMC - NIH
In this review, we summarize various signaling pathways mediated by β-arrestins and highlight the physiologic effects of β-arrestin-dependent signaling.
[107]
Biased agonism: An emerging paradigm in GPCR drug discovery
Biased agonism, or functional selectivity, is when ligands selectively activate one pathway of a GPCR over another, changing the linear spectrum of GPCR ...
[108]
Molecular mechanisms of excitotoxicity and their relevance to ...
Excitotoxicity is defined as cell death resulting from the toxic actions of excitatory amino acids. Because glutamate is the major excitatory neurotransmitter ...Missing: historical | Show results with:historical
[109]
Brain Lesions, Obesity, and Other Disturbances in Mice Treated with ...
Brain Lesions, Obesity, and Other Disturbances in Mice Treated with Monosodium Glutamate. John W. OlneyAuthors Info & Affiliations. Science. 9 May 1969. Vol 164 ...
[110]
Editorial: Excitotoxicity Turns 50. The Death That Never Dies - PMC
The series of articles of this Research Topic collection celebrates the 50th anniversary of the seminal work published by John W. Olney in 1969 and the ...Missing: 1980 | Show results with:1980
[111]
Molecular mechanisms of excitotoxicity and their relevance to the ...
May 19, 2025 · When energy supply is low, intracellular glutamate leaks outside the cell due to failure of energy-dependent transport mechanisms [19]. When ...
[112]
Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward ...
The molecular mechanism that triggers excitotoxicity involves alterations in glutamate and calcium metabolism, dysfunction of glutamate transporters, and ...
[113]
Dysfunctional Astrocyte Metabolism: A Driver of Imbalanced ... - MDPI
Impaired glutamate uptake and conversion to glutamine within astrocytes leads to elevated extracellular glutamate, promoting excitotoxicity. Altered glycogen ...
[114]
Amyloid β, Glutamate, Excitotoxicity in Alzheimer's Disease
Aβ oligomers interfere with NMDA signaling, inducing an internalization of postsynaptic NMDANR2A subunits (dotted). Due to interference of Aβ with EAAT, ...Glutamate And Synaptic... · Synaptic Plasticity In... · Glutamate Hypothesis And...
[115]
Amyloid Beta-Related Alterations to Glutamate Signaling Dynamics ...
During the NRHyper phase, Aβ potentiates glutamate release and increases NMDA activation and sensitivity to glutamate. This leads to partial membrane ...
[116]
The role of pathological tau in synaptic dysfunction in Alzheimer's ...
Nov 10, 2021 · The pathological tau induces synaptic dysfunction in several ways, including reducing the mobility and release of presynaptic vesicles, ...
[117]
Dopamine depletion weakens direct pathway modulation of SNr ...
Jun 15, 2024 · Dopamine loss disrupts the balance of activity between the direct and indirect pathways, hypothesized to contribute to motor dysfunction in ...
[118]
Inhibitory and Excitatory Imbalance in Neurodegenerative Diseases
Aug 14, 2025 · In PD, dopaminergic degeneration disrupts the balance of excitatory and inhibitory inputs in basal ganglia circuits. ... Parkinson's disease ...
[119]
Revisiting Glutamate Excitotoxicity in Amyotrophic Lateral Sclerosis ...
May 21, 2024 · Most of our understanding of increased glutamate release in ALS comes from the mutant SOD1 G93A Tg mouse model. Transporters for different ...
[120]
Rapamycin prevents the mutant huntingtin-suppressed GLT-1 ... - NIH
The result showed significantly decreased glutamate uptake in astrocytes expressing mutant Htt, which was closely correlated with altered expression of GLT-1 ( ...Glutamate Uptake Assay · Figure 2 · Figure 3
[121]
C5aR1 signaling promotes region‐ and age‐dependent synaptic ...
Jan 26, 2024 · Complement-mediated synaptic pruning has been associated with this excessive loss of synapses in AD. Here, we investigated the effect of C5aR1 ...3.2 Absence Of C5ar1 Rescues... · 3.4 C5a-C5ar1 Influences... · 3.6 Astrocytes Contribute To...
[122]
Synaptic pruning genes networks in Alzheimer's disease - PubMed
Jun 14, 2025 · This study comprehensively analyzes the expression of SP-related genes, including complement system components (C1QA, C1QB, C1QC, C1S, C1R, C3), microglial ...