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Granule cell

Granule cells are a class of small, densely packed neurons distinguished by their small cell bodies (typically 5-18 μm in diameter depending on the region), short claw-like dendrites, and unmyelinated axons, serving as the most abundant neuronal type in the mammalian brain and comprising over 99% of all cerebellar neurons. Found primarily in the granule cell layer of the cerebellum, the dentate gyrus of the hippocampus, the granule cell layer of the olfactory bulb, and the superficial layer of the dorsal cochlear nucleus, these neurons exhibit region-specific morphologies and functions but share a common role in integrating sensory and contextual inputs for higher-order processing.^[1]^[2]^[3] In the cerebellum, granule cells originate from progenitors in the upper rhombic lip during embryonic development, undergoing massive proliferation in the external granular layer before migrating inward to form the mature granule cell layer by postnatal day 25 in mice, resulting in an estimated 70 million cells per cerebellum. These glutamatergic excitatory neurons receive convergent inputs from mossy fibers via their T-shaped dendritic claws and extend parallel fibers that ascend to the molecular layer, synapsing onto Purkinje cell dendrites and inhibitory interneurons to relay mossy fiber signals in a feedforward excitatory pathway essential for cerebellar circuitry. This organization enables granule cells to support motor coordination, learning, and error correction by transforming diverse mossy fiber patterns into sparse, combinatorial representations across their parallel fiber outputs.^[2]^[4]^[5] Within the hippocampal dentate gyrus, granule cells function as the principal output neurons of this subregion, featuring cone-shaped apical dendrites that extend into the molecular layer to receive perforant path inputs from the entorhinal cortex, while their mossy fiber axons project to CA3 pyramidal cells. Characterized by ongoing adult neurogenesis—where new granule cells are generated from subgranular zone progenitors and integrate into existing circuits over weeks—these neurons employ sparse firing to perform pattern separation, orthogonalizing similar input representations to facilitate distinct memory encoding and reduce interference in the trisynaptic hippocampal circuit. Disruptions in dentate granule cell function or neurogenesis have been linked to impairments in spatial memory and contextual learning, underscoring their role in cognitive flexibility.^[6]^[7] In the olfactory bulb, granule cells represent a diverse inhibitory population, often lacking a prominent axon (anaxonic) and utilizing GABA as their primary neurotransmitter to form reciprocal dendrodendritic synapses with mitral and tufted cells in the external plexiform layer. These periglomerular and deeper granule cells modulate odor-evoked activity by providing lateral inhibition, enhancing odor discrimination and sensory contrast through feedback and feedforward mechanisms that sharpen glomerular output patterns. Unlike their excitatory counterparts in other regions, olfactory granule cells also undergo adult neurogenesis from the subventricular zone, contributing to experience-dependent plasticity in olfactory processing.^[3]^[8]

Overview

Definition and characteristics

Granule cells represent the smallest and most abundant class of neurons in the vertebrate brain, characterized by their diminutive size and high packing density that enables extensive neural computation. These neurons typically possess a compact soma with a diameter ranging from 5 to 10 μm, allowing for dense layering in specific brain structures.^[9]^[10] In humans, the cerebellum alone contains approximately 69 billion granule cells (as of 2009 estimates), underscoring their numerical dominance and contribution to the brain's overall neuronal population, which exceeds half of all neurons.^[11]^[12] A defining feature of granule cells is their minimalist morphology, including a small soma, limited dendritic arborization with typically 3 to 5 short dendrites, and elongated unmyelinated axons that form either extensive parallel fiber networks or localized connections depending on the region. In the cerebellum, these cells are excitatory and release glutamate as their primary neurotransmitter, facilitating signal integration.^[9]^[13] In contrast, granule cells in regions such as the olfactory bulb are inhibitory, utilizing GABA as their neurotransmitter to modulate sensory processing.^[14] This variability in neurochemistry highlights their adaptability while maintaining core structural traits that support roles as interneurons or relay cells in sensory-motor pathways.^[15] The granule cell was first described in the 1870s by Camillo Golgi, who utilized his newly developed black reaction staining method to visualize the fine anatomy of the human cerebellum, revealing these neurons as key components of the granular layer.^[16] Within the cerebellum, granule cells constitute approximately 99% of all neurons, providing the substrate for its vast computational capacity in coordinating movement and learning.^[2] Granule cells are present across various brain regions, including the cerebellum, olfactory bulb, and hippocampus, where they contribute to localized circuit functions.^[15]

Distribution in the brain

Granule cells are predominantly located in the granular layer of the cerebellum, where they form the vast majority of neurons in this structure, estimated at approximately 69 billion cells in humans (as of 2009).^[11] They are also found in the dentate gyrus of the hippocampus, with around 1.2 \times 10^6 granule cells in rodents and approximately 9 \times 10^6 in humans.^[7]^[17] In the olfactory bulb, granule cells populate both the glomerular and granule cell layers, constituting the largest neuronal population in this structure and comprising over 90% of its neurons in many mammals.^[18] Additionally, granule cells reside in the superficial layer of the dorsal cochlear nucleus (DCN) in the brainstem, where they integrate auditory and nonauditory inputs.^[19] The cerebellum harbors the largest population of granule cells, accounting for over half of all neurons in the human brain and playing a key role in motor coordination.^[12] In contrast, the dentate gyrus contains a relatively smaller but functionally significant number, supporting memory formation through pattern separation.^[7] The olfactory bulb's granule cells, as the most abundant type, facilitate sensory processing in olfaction, while those in the DCN contribute to auditory signal integration.^[18]^[20] Granule cells exhibit evolutionary conservation across all vertebrates, with their presence in cerebellar-like structures dating back to early chordates and notable expansions in mammalian lineages to enhance complex sensory-motor integration.^[21]^[22] Rare ectopic occurrences of granule-like cells have been identified in other brain regions, such as the cerebral cortex, where they appear in healthy individuals and may represent a minor, normally occurring population rather than pathological anomalies, as evidenced by single-nucleus transcriptomic analyses in 2022.^[23]

Morphology

General structural features

Granule cells are characterized by a small, round soma with a diameter typically ranging from 5 to 12 μm, making them among the smallest neurons in the central nervous system in contrast to larger projection neurons such as pyramidal cells, which can exceed 20-50 μm in diameter.^[10]^[15] The nucleus within the soma is relatively large and oval, occupying a substantial portion of the cell body, while the surrounding cytoplasm is sparse and contains few organelles.^[24] Their dendrites are short and claw-like, usually numbering three to four per cell with a total length of 10-50 μm, facilitating multi-input convergence such as up to four mossy fiber rosettes in cerebellar granule cells.^[3]^[25] The axon is thin and unmyelinated, often forming parallel fibers that extend considerable distances—up to several millimeters in the cerebellum—while creating en passant synapses; in other types, such as olfactory granule cells, axons are short and local.^[10] At the ultrastructural level, granule cells exhibit a high density of ribosomes in their cytoplasm, supporting robust protein synthesis, and can be identified via immunohistochemistry using markers like calbindin in dentate gyrus granule cells or GAD67 in olfactory granule cells.^[26]^[27]^[28]

Type-specific morphology

Granule cells display region-specific morphological variations that reflect their integration into local neural circuits, with differences in dendritic arborization, axonal projections, and spine distribution. In the cerebellum, granule cells possess 3 to 5 short, claw-like dendrites, each extending 12 to 20 μm from a small soma of 5 to 10 μm diameter, positioned to receive excitatory inputs from mossy fiber rosettes within glomerular structures.^[29] Their single axon ascends through the Purkinje cell layer before bifurcating in a T-shaped manner to form parallel fibers, which traverse the molecular layer for distances averaging 6 mm and establish numerous en passant synapses onto Purkinje cell dendrites.^[29] Dentate gyrus granule cells in the hippocampus feature a multipolar dendritic architecture, typically with one primary apical dendrite branching into spiny processes that span the molecular layer, achieving a total dendritic length of approximately 3,500 μm and individual branches up to 100 μm, thereby sampling inputs from the entorhinal cortex and other afferents.^[30]^[31] These cells' mossy fiber axons extend robustly to the CA3 pyramidal cell layer, terminating in large, complex giant boutons (5 to 10 μm in diameter) that facilitate strong excitatory connections.^[31] Olfactory bulb granule cells, located in the granule cell layer, exhibit short, unbranched or minimally branched dendrites adorned with a high density of spines, enabling reciprocal dendrodendritic synapses directly with mitral and tufted cell dendrites in the external plexiform layer; unlike other granule cell types, they lack a distinct axon, relying instead on dendritic output for signaling.^[32] This spine-rich, gemmous morphology supports their role in lateral inhibition and is modulated by sensory experience, with spine numbers increasing in enriched odor environments.^[32] Granule cells in the dorsal cochlear nucleus encompass diverse subtypes, including traditional multipolar forms with 4 to 5 short dendrites and ascending axons, as well as specialized unipolar brush cells characterized by a single dendrite terminating in a brush-like tuft of dendrioles (forming large synaptic junctions of 12 to 40 μm²) and short, locally branching axons that create intrinsic mossy fiber circuits within the granular layer.^[33] These adaptations are underscored by quantitative disparities, such as cerebellar dendrites limited to about 20 μm versus the more extensive 100 μm branches in dentate gyrus cells, and the notably higher spine density in olfactory bulb granule cells compared to their sparser counterparts elsewhere.^[29]^[31]^[32]

Development and Neurogenesis

Embryonic development

Granule cell progenitors in the cerebellum and dorsal cochlear nucleus originate from the upper rhombic lip, a germinal zone in the dorsal hindbrain expressing the transcription factor Atoh1, which is essential for their specification to an excitatory granule neuron fate.^[34] In contrast, progenitors for dentate gyrus granule cells arise from the primary dentate neuroepithelium adjacent to the cortical hem, a region of the ventricular zone, beginning around embryonic day (E) 10.5 in mice.^[35] Olfactory bulb granule cells similarly derive from embryonic progenitors in the lateral ganglionic eminence, part of the subventricular zone derived from the ventral telencephalic ventricular zone.^[36] In mice, cerebellar granule cell precursors emerge from the rhombic lip around E9.5 and undergo tangential migration to form the external granule layer (EGL) by E13, with the EGL covering the cerebellar surface by E15 and proliferating actively from late embryonic stages through postnatal day (P) 0.^[2] These precursors then migrate inward to the internal granule layer between P0 and P21. For dentate gyrus granule cells, precursors proliferate in the dentate neuroepithelium from E10 to E12.5, initiate migration around E14 to E15.5, and begin condensing into the granule cell layer by E18.5 to P1, with most embryonic maturation completed by birth.^[35] Migration mechanisms differ by region: in the cerebellum, precursors first migrate tangentially from the rhombic lip to the EGL, followed by radial migration of postmitotic granule cells along Bergmann glial fibers from the inner EGL to the internal granule layer.^[37] In the dentate gyrus, granule cell precursors undergo radial migration guided by radial glial scaffolds from the ventricular zone toward the forming granule cell layer.^[35] Maturation milestones include postnatal axon extension, with cerebellar granule cells forming parallel fiber axons in the molecular layer between P7 and P14.^[2] Synapse formation begins prenatally but intensifies postnatally, with parallel fibers establishing connections to Purkinje cell dendrites primarily between P10 and P21.^[38] Apoptosis affects approximately 5% of granule cell progenitors in the external granular layer (EGL), contributing to population regulation during development, with peaks around P7 to P14 in the cerebellum.^[39] In humans, the cerebellar EGL forms between the 9th and 11th gestational weeks and persists with high proliferation until the 34th gestational week, maintaining stable width through the first postnatal month before gradually decreasing and fully disappearing by the 11th postnatal month, longer than the rapid postnatal timeline observed in mice.^[40]

Adult neurogenesis

Adult neurogenesis refers to the ongoing generation of new neurons in the mature brain, with granule cells being prominently produced in specific neurogenic niches. This process contributes to neural plasticity, particularly in regions involved in learning and sensory processing. In the hippocampus, new granule cells arise from the subgranular zone (SGZ) of the dentate gyrus, where neural progenitors divide to replenish the granule cell layer. Similarly, in the olfactory system, granule cells are generated in the subventricular zone (SVZ) and migrate through the rostral migratory stream to integrate into the olfactory bulb's granule cell layer.^[41]^[42] The rate of granule cell production varies by species and region. In adult humans, the dentate gyrus adds approximately 700 new granule cells per day, representing an annual turnover of about 1.75% of the renewing neuronal population. In rodents, the olfactory bulb receives a continuous influx of around 50,000 new granule cells per day, supporting ongoing circuit refinement in response to olfactory inputs. These rates underscore the scale of adult neurogenesis, though only a subset of newborn cells survive and fully integrate into functional networks.^[43]^[44] The neurogenic process for granule cells involves sequential stages of proliferation, differentiation, migration, and maturation. It begins with the asymmetric division of Nestin-expressing neural stem cells in the SGZ or SVZ, generating intermediate progenitors that differentiate into doublecortin-positive (Dcx+) neuroblasts. These neuroblasts then migrate short distances in the dentate gyrus or along the rostral migratory stream to the olfactory bulb, where they extend dendrites and axons to form synapses with principal neurons and interneurons. Key regulatory mechanisms include brain-derived neurotrophic factor (BDNF), which promotes progenitor survival and dendritic growth, and Notch signaling, which maintains the stem cell pool and prevents premature differentiation.^[45]^[46]^[47] Maturation timelines differ between sites but emphasize a period of heightened plasticity. In the dentate gyrus, newborn granule cells transition from progenitors to functional, synaptically active neurons over 4-6 weeks, during which they exhibit enhanced excitability and synaptic remodeling critical for circuit incorporation. In the olfactory bulb, the process is similarly protracted, with new granule cells achieving maturity in 3-4 weeks post-migration, enabling continuous turnover of inhibitory interneurons. This temporal window allows adult-born cells to fine-tune network dynamics before stabilizing.^[48]^[42] Recent research highlights the functional contributions of adult-born granule cells. Studies from 2022 and 2023 demonstrate that these cells in the dentate gyrus improve stimulus encoding by enhancing the fidelity of population-level signals and support pattern separation, a computation that distinguishes similar experiences to aid memory formation. Additionally, a 2012 investigation revealed that early-stage adult-born dentate granule cells exhibit a transient GABAergic phenotype, upregulating GABA synthesis enzymes in their soma to modulate local inhibition during initial network integration. These insights, drawn from rodent models, emphasize the role of young neurons in adaptive plasticity.^[49]^[50]^[51] Adult neurogenesis is modulated by environmental and physiological factors that influence proliferation and survival rates. Physical exercise and environmental enrichment robustly increase granule cell production in both the dentate gyrus and olfactory bulb, partly through elevated BDNF levels that enhance progenitor proliferation and neuronal survival. Conversely, chronic stress and depression suppress neurogenesis by activating glucocorticoid pathways that inhibit stem cell division and promote newborn cell death, thereby reducing the pool of integrating neurons. These modulations link lifestyle interventions to brain plasticity outcomes.^[52]^[53]

Physiology

Electrophysiological properties

Granule cells across brain regions exhibit characteristic resting membrane potentials typically ranging from -60 to -70 mV, reflecting their compact size and resulting low input resistance, which limits passive signal spread and enhances excitability to synaptic inputs.^[54] Action potentials in granule cells are narrow, with durations of 0.5-1 ms, enabling high firing rates that can reach up to 500 Hz during bursts, particularly in cerebellar granule cells responding to mossy fiber inputs.^[56]^[57] These spikes are followed by afterhyperpolarization mediated by small-conductance calcium-activated potassium (SK) channels, which regulate firing frequency and prevent excessive depolarization. Key ionic currents shape these behaviors: a persistent sodium (Na+) current supports pacemaking activity, maintaining subthreshold depolarization for rhythmic firing in both cerebellar and hippocampal granule cells.^[59] T-type calcium (Ca2+) channels, particularly Cav3.2, contribute to burst firing by generating low-threshold spikes that amplify excitability during transient inputs.^[60] In dentate gyrus granule cells, the hyperpolarization-activated cation current (Ih), carried by HCN channels, promotes resonance at theta frequencies, tuning cells to oscillatory network rhythms.^[61] Excitability profiles vary by type and maturity; cerebellar granule cells typically display tonic firing patterns with linear increases in rate against current injection, supporting reliable sensory relay.^[62] In contrast, immature dentate gyrus granule cells are hyperexcitable due to depolarizing GABAergic responses, which drive enhanced bursting before the developmental shift to hyperpolarizing inhibition.^[63] Patch-clamp recordings have revealed subthreshold oscillations in granule cells, such as theta-frequency resonances in olfactory bulb and hippocampal subtypes, underlying their integration into oscillatory circuits.^[64] Recent 2025 computational models predict that hippocampal granule cells respond robustly to extracellular fields, with multiscale simulations showing field-induced activation patterns that modulate excitability without altering intrinsic spike properties.^[65]

Synaptic transmission

Granule cells receive primarily excitatory synaptic inputs that activate AMPA and NMDA receptors on their dendrites. In the cerebellum, these inputs arise from glutamatergic mossy fibers, with each granule cell integrating inputs from approximately four mossy fibers within glomerular structures, enabling high convergence that amplifies sensory signals.^[66]^[67]^[68] These mossy fiber-granule cell synapses exhibit rapid transmission mediated by AMPA receptors, with NMDA receptors contributing to longer-lasting components during high-frequency activity.^[69]^[70] In the dentate gyrus, excitatory inputs come from the perforant path of the entorhinal cortex. In the olfactory bulb, granule cells receive excitatory glutamatergic inputs from mitral and tufted cells via dendrodendritic synapses. Inhibitory inputs to granule cells are predominantly GABAergic, originating from local interneurons. Cerebellar granule cells receive phasic and tonic inhibition from Golgi cells, which regulate the balance of excitatory drive and prevent overexcitation.^[71]^[72] In the olfactory bulb, granule cells form reciprocal dendrodendritic synapses with mitral cells, where GABA release provides mutual inhibition to shape odor processing.^[3] Granule cell outputs differ by region: in the cerebellum and dentate gyrus, they are glutamatergic, projecting to downstream principal neurons via specialized axons. In the cerebellum, parallel fibers from granule cells synapse onto Purkinje cells, conveying recoded mossy fiber information.^[69] In the dentate gyrus, granule cell axons form mossy fibers that target CA3 pyramidal cells, often featuring filopodial extensions for additional synaptic contacts.^[73]^[74] In the olfactory bulb, granule cell outputs are GABAergic, inhibiting mitral cells through reciprocal dendrodendritic connections to modulate sensory output. Synaptic plasticity at granule cell outputs is critical for circuit adaptation, particularly long-term potentiation (LTP) and depression (LTD). At cerebellar parallel fiber-Purkinje cell synapses, LTD is induced by coincident activation of parallel and climbing fibers, reducing synaptic strength to refine motor learning.^[75]^[76] Endocannabinoid signaling mediates retrograde suppression at these synapses, with climbing fiber activity enhancing endocannabinoid release to modulate presynaptic glutamate release.^[77] LTP can also occur postsynaptically, strengthening transmission during patterned activity.^[78] Granule cell synapses feature high densities of AMPA receptors to support fast excitatory transmission, with estimates of 20-50 receptors per synapse ensuring reliable signaling.^[79]^[80] Spillover of glutamate from nearby release sites further activates these AMPA receptors, prolonging postsynaptic responses without compromising speed. A 2025 study revealed that the orphan G protein-coupled receptor Gpr85, enriched at cerebellar granule cell synapses, modulates excitability by altering synaptic properties; its deficiency leads to heightened neuronal firing and enhanced behavioral responses to stimuli.^[81]^[82]

Functions in Neural Circuits

Cerebellar granule cells

Cerebellar granule cells (GrCs) integrate diverse sensory and motor inputs from mossy fibers, which originate from precerebellar nuclei and convey information about ongoing movements, sensory stimuli, and contextual cues. These inputs synapse onto the dendrites of GrCs in the granular layer, where each GrC receives excitatory connections from approximately four to five mossy fiber rosettes, enabling the convergence of multimodal signals. GrCs then relay this processed information through their parallel fibers, which extend across the molecular layer to form excitatory synapses onto Purkinje cells (PCs), the primary output neurons of the cerebellar cortex. This arrangement allows GrCs to expand the input space via combinatorial coding, where the sparse connectivity—each mossy fiber diverging to hundreds of GrCs, while each GrC contacts a single mossy fiber—generates a high-dimensional representation of inputs, facilitating the discrimination of subtle patterns essential for precise motor control.^[83]^[12] In motor learning, GrCs generate sparse and decorrelated activity patterns that support error signaling and predictive computations within the cerebellar circuit. By producing low-overlap representations across ensembles, GrCs enable the cerebellum to distinguish between similar inputs, which is crucial for associating sensory contexts with corrective outputs from climbing fibers. A 2024 study demonstrated that during reward-timing tasks, GrCs develop ramping activity that anticipates events over seconds-long intervals, integrating mossy fiber predictions with climbing fiber teaching signals to refine PC responses and facilitate learning of temporal associations between actions and rewards. This ramping emerges as mice acquire predictive behaviors, with GrC ensembles showing graded increases in firing rates that align with expected reward delivery, thereby supporting the cerebellum's role in forward modeling of motor outcomes.^[84] GrCs receive inhibitory modulation from local interneurons, including Golgi cells and Lugaro cells, which fine-tune their output timing and population dynamics. Golgi cells provide direct GABAergic inhibition onto GrC dendrites, suppressing excessive excitation and promoting burst-pause patterns that enhance signal fidelity. Lugaro cells, which also express glycine transporters, contribute to this network by inhibiting Golgi cells, indirectly regulating GrC activity. Recent 2025 research on GlyT2-positive interneurons—encompassing Golgi and Lugaro cells—reveals that their glycinergic and GABAergic inhibition controls the temporal patterning and variability of GrC population responses, reducing timing jitter in synchronized bursts during sensory-motor tasks and ensuring reliable transmission to PCs.^[85]^[86] Behaviorally, GrCs are vital for predictive control of movements, allowing the cerebellum to anticipate sensory consequences and adjust trajectories in real time. Disruption of GrC function impairs this capability, as evidenced by loss-of-function models where selective ablation or genetic knockout in GrC progenitors leads to severe ataxia, characterized by uncoordinated gait, tremor, and dysmetria due to failed integration of predictive signals. These models underscore the necessity of GrC-mediated expansions for maintaining motor precision, with deficits mirroring human cerebellar disorders.^[87] While no major subtypes of cerebellar GrCs are widely recognized, ectopic mature GrCs—displaced from the standard granular layer—have been observed to contribute to baseline network activity. These cells, potentially arising from developmental anomalies, maintain tonic firing that sets a permissive state for input processing, influencing overall circuit excitability without dominating task-specific responses. A 2022 study highlighted their role in sustaining low-level activity in otherwise quiescent ensembles, aiding in the maintenance of cerebellar homeostasis.^[88]

Dentate gyrus granule cells

Dentate gyrus granule cells (GCs) are principal neurons in the hippocampal dentate gyrus, receiving inputs from the entorhinal cortex via the perforant path and projecting to CA3 pyramidal cells through mossy fibers, forming a key component of the trisynaptic circuit essential for memory processing.^[89] These cells exhibit sparse firing, with low baseline activity rates typically below 0.1 Hz, which contributes to their role in transforming similar inputs into distinct representations.^[90] A primary function of dentate gyrus GCs is pattern separation, where they convert overlapping entorhinal cortical inputs into orthogonal outputs to CA3, minimizing interference in memory storage. This process relies on sparse firing patterns that decorrelate similar stimuli and lateral inhibition mediated by GABAergic interneurons, such as basket cells, which suppress overlapping activity among GCs.^[89] Computational and experimental evidence shows that this mechanism enhances the orthogonality of population activity, with studies demonstrating improved discrimination of similar contexts in rodents when GC activity is intact.^[91] Dentate gyrus GCs include morphological subtypes, such as semilunar granule cells (SGCs), which possess hilar basal dendrites and are sparsely distributed near the granule cell layer-hilus border. A 2024 study identified SGCs as preferentially recruited during contextual memory formation, showing higher activation in fear conditioning tasks compared to typical GCs, potentially due to their unique dendritic integration of hilar inputs.^[92] Mossy cells, excitatory hilar neurons, modulate GC activity through feedback projections, providing glutamatergic drive that can enhance or suppress ensembles during memory encoding.^[92] Adult-born GCs, generated via hippocampal neurogenesis, integrate into dentate circuits over weeks and enhance pattern separation by improving the fidelity of temporal stimulus encoding in population activity. A 2023 study in mice demonstrated that immature adult-born GCs, despite their higher excitability and variability, boost discrimination of similar time-dependent stimuli, such as sequential odors, by increasing signal reliability across the network.^[49] These cells initially express transient GABA-mediated excitation due to delayed chloride transporter expression, which regulates network excitability during integration and supports refined input-output transformations.^[49] Behaviorally, dentate gyrus GCs are critical for spatial navigation and contextual fear conditioning, where they enable discrimination of similar environments to avoid generalization of fear responses. Optogenetic ablation or silencing of GCs impairs performance in spatial tasks like the Morris water maze and leads to deficits in distinguishing safe from dangerous contexts in fear conditioning paradigms.^[93] For instance, post-training ablation of adult-generated GCs degrades previously acquired contextual discrimination without affecting overall memory retrieval.^[94] Multiscale computational models of dentate gyrus GCs simulate their activation in response to extracellular electrical stimulation, integrating biophysical details from ion channels to network interactions to predict spike timing and population dynamics. A 2025 Frontiers study developed such a model, showing that GC responses to extracellular spikes depend on dendritic morphology and synaptic clustering, providing insights into how stimulation parameters influence memory-related circuit activity.^[65] These models highlight the role of sparse coding in maintaining orthogonal representations under varying input conditions.

Olfactory bulb granule cells

Olfactory bulb granule cells (GCs) are the most abundant interneurons in the mammalian olfactory bulb (OB), comprising up to 90% of all local circuit neurons and primarily located in the granule cell layer.^[18] They outnumber the principal output neurons, mitral and tufted cells, at a ratio of approximately 50:1 to 100:1, enabling extensive inhibitory control over olfactory processing.^[95] Unlike many other granule cells, OB GCs are axonless and feature spine-covered basal dendrites that extend into the external plexiform layer, where they form reciprocal dendrodendritic synapses with the lateral dendrites of mitral and tufted cells.^[96] These GCs also interact reciprocally with periglomerular cells, contributing to contrast enhancement at the glomerular level by modulating excitatory inputs from olfactory sensory neurons.^[97] In the OB circuit, GCs provide feedback and lateral inhibition to mitral and tufted cells, refining odor representations through GABAergic transmission at dendrodendritic synapses.^[98] This inhibition is often NMDA receptor-dependent, where glutamate release from mitral/tufted cell dendrites excites GC spines via AMPA and NMDA receptors, triggering reciprocal GABA release that suppresses mitral/tufted cell activity and controls gain in odor-evoked responses. Such NMDA-mediated reciprocal inhibition enhances the dynamic range of principal cell firing, preventing saturation during strong odor stimuli and promoting sparse coding.^[99] Lateral inhibition mediated by GCs specifically targets coactive glomerular columns, linking related odor features while suppressing uncorrelated activity to sharpen perceptual boundaries.^[96] GCs play essential roles in odor discrimination by implementing lateral inhibition that enhances contrast between similar odorants, as demonstrated in computational models and physiological recordings.^[100] Disinhibition of GCs, achieved through optogenetic silencing, accelerates odor discrimination in mice, reducing response times for both dissimilar and highly similar odor pairs without altering sensitivity.^[101] In knockout models lacking key regulators of GC function, such as CPEB4-deficient mice with reduced neonate-born GCs, animals exhibit impaired spontaneous discrimination of novel odors despite intact short-term memory and sensitivity.^[102] Similarly, ablation of adult-born GCs impairs fine odor discrimination, underscoring their necessity for behavioral performance in tasks requiring distinction of structurally similar scents.^[103] Synaptic plasticity in OB GCs is experience-dependent, supporting odor learning through strengthening of dendrodendritic connections.^[104] Odor enrichment induces long-term potentiation-like changes in GC spines, increasing dendritic complexity and synaptic efficacy in response to repeated exposure, which refines odor tuning in alert animals.^[105] Adult-born GCs derived from the subventricular zone (SVZ) integrate into these circuits, with their survival and plasticity modulated by olfactory experience to enhance discrimination of behaviorally relevant odors (see Adult neurogenesis).^[106] Recent studies suggest GC networks contribute to building internal models of olfactory scenes by integrating sensory inputs with contextual feedback, analogous to predictive processing in motor systems but tuned for dynamic sensory adaptation.^[107]

Dorsal cochlear nucleus granule cells

Granule cells in the dorsal cochlear nucleus (DCN) form a critical component of the granule cell layer, integrating auditory and non-auditory inputs to modulate auditory signal processing in the brainstem. These cells primarily receive excitatory mossy fiber inputs from unmyelinated type II auditory nerve fibers, collaterals from central auditory nuclei, and somatosensory projections from the dorsal column and spinal trigeminal nuclei.^[20] Their axons, known as parallel fibers, extend superficially to synapse onto principal neurons such as pyramidal (fusiform) cells and interneurons like cartwheel cells, facilitating spectral processing and feature extraction of complex sounds.^[20] This circuit architecture allows granule cells to convey multimodal information, enhancing the DCN's role in refining auditory representations.^[108] Among the subtypes of DCN granule cells, unipolar brush cells (UBCs) stand out for their specialized morphology and function, characterized by a single dendrite ending in a brush-like tuft that receives large, calyx-like glutamatergic synapses from mossy fibers. UBCs are divided into ON and OFF subtypes based on their postsynaptic responses: ON UBCs, expressing mGluR1α receptors, generate prolonged excitatory currents via AMPA and metabotropic glutamate receptor activation, while OFF UBCs, lacking mGluR1α, produce inhibitory responses through mGluR2-coupled GIRK channels.^[109] These subtypes enable delay-line coding, where sustained postsynaptic activity outlasts brief mossy fiber bursts, supporting precise temporal encoding essential for sound localization. Unlike typical small granule cells, UBCs project intrinsic mossy fibers to other granule cells, amplifying feedforward excitation with low connection probabilities around 0.12.^[109] Functionally, DCN granule cells encode temporal patterns in auditory stimuli, contributing to echo suppression through forward masking mechanisms that inhibit responses to subsequent sounds, as observed in principal cell responses modulated by parallel fiber activity.^[20] They play a key role in processing binaural cues by integrating head and pinna position signals with auditory inputs, aiding in spatial localization of sound sources.^[109] Inhibitory modulation arises disynaptically, as parallel fibers excite GABAergic and glycinergic cartwheel cells, which in turn inhibit fusiform cells, sharpening spectral selectivity; disruptions in this pathway, such as reduced glycinergic inhibition following cochlear damage, lead to hyperactivity in fusiform cells and tinnitus-like symptoms in animal models.^[108] Recent studies highlight the involvement of DCN granule cells in multimodal integration of auditory and somatosensory inputs, potentially modulating auditory processing during head movements, though this area remains less explored compared to granule cells in other nuclei like the cerebellum or olfactory bulb.^[20]

Pathological Roles

In neurodegenerative diseases

In Alzheimer's disease (AD), dentate gyrus granule cells exhibit progressive loss, with studies in mouse models such as APP/PS1KI showing age-dependent neuronal depletion in the granule cell layer, contributing to hippocampal atrophy and cognitive decline.^[110] Aberrant mossy fiber sprouting from surviving granule cells into the inner molecular layer has been observed in AD transgenic models like hAPP-J20 mice, potentially leading to disrupted hippocampal circuitry and exacerbated memory impairments.^[111] Additionally, tau pathology in dentate gyrus mossy cells and granule cells promotes hyperexcitability and impairs pattern separation, a critical function for distinguishing similar experiences, as evidenced by tau accumulation models where soluble tau disrupts dendritic plasticity and synaptic integration.^[112]^[113] Cerebellar granule cells are implicated in several proteinopathies, with atrophy in the granule layer correlating with motor deficits in spinocerebellar ataxias (SCAs). In SCA models, such as those involving CAPN1 mutations, granule cell loss disrupts cerebellar circuitry and contributes to ataxic gait and coordination impairments, independent of primary Purkinje cell degeneration.^[114] A 2025 study in Nature Neuroscience revealed TDP-43 mislocalization in aged cerebellar neurons, leading to splicing dysregulation and heightened vulnerability to neurodegeneration, linking aging-related changes to progressive motor dysfunction in cerebellar pathologies.^[115] Mechanistically, amyloid-beta (Aβ) toxicity directly impairs adult neurogenesis in the dentate gyrus, reducing progenitor proliferation and maturation of granule cells in AD models, thereby limiting the brain's regenerative capacity.^[116] Oxidative stress further exacerbates this by shortening granule cell dendrites and reducing arbor complexity, as demonstrated in superoxide dismutase-deficient models where reactive oxygen species diminish dendritic length and synaptic connectivity.^[117] These processes collectively drive granule cell dysfunction in neurodegenerative contexts. Therapeutic strategies targeting granule cell preservation hold promise for mitigating cognitive and motor symptoms; for instance, PPARγ agonists like rosiglitazone normalize dentate granule cell excitability and synaptic plasticity in AD mouse models, improving memory performance.^[118] Boosting hippocampal neurogenesis through pharmacological or stem cell interventions has also shown potential to rescue granule cell integration and alleviate AD-related deficits, while similar approaches in SCA models aim to preserve cerebellar granule populations to restore motor coordination.^[119]

In epilepsy and mood disorders

In epilepsy, particularly temporal lobe epilepsy (TLE), aberrant neurogenesis in the dentate gyrus of the hippocampus leads to excessive production of granule cells, which contribute to mossy fiber sprouting and the formation of ectopic excitatory synapses. These sprouted mossy fibers form recurrent excitatory connections onto neighboring granule cells and inhibitory interneurons, thereby promoting hyperexcitability and seizure propagation within the dentate network.^[120]^[121] In TLE animal models, such as those induced by pilocarpine or kainate, this pathological neurogenesis is accompanied by granule cell dispersion, where newly generated cells migrate ectopically into the hilus, further disrupting normal circuit organization and enhancing seizure susceptibility.^[122] Granule cell dysfunction also plays a central role in mood disorders, including major depressive disorder and anxiety. In depression, chronic stress reduces adult neurogenesis in the dentate gyrus, leading to fewer mature granule cells and impaired hippocampal plasticity, which correlates with depressive symptoms.^[123] Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, counteract this by promoting granule cell proliferation and survival through upregulation of brain-derived neurotrophic factor (BDNF) signaling, which enhances synaptic integration and restores neuroplasticity.^[124] In anxiety disorders, diminished granule cell function impairs pattern separation in the dentate gyrus, resulting in overgeneralization of fear responses, where similar but distinct stimuli elicit excessive anxiety-like behaviors.^[125] Mechanistically, these disorders involve an imbalanced excitation-inhibition ratio in granule cell circuits, where excessive excitatory inputs from sprouted mossy fibers overwhelm inhibitory controls from interneurons, fostering hyperexcitability in epilepsy.^[126] In epileptic conditions, morphological changes such as shorter dendrites in dispersed granule cells reduce dendritic arborization and input integration, limiting the cells' ability to filter noisy signals and exacerbating circuit instability, as evidenced in recent computational models of TLE.^[122] Behaviorally, hypofunction of dentate granule cells impairs fear extinction, prolonging anxiety by hindering the discrimination of safe versus threatening contexts.^[125] Rapid-acting antidepressants like ketamine alleviate depression by selectively activating immature adult-born granule cells, enhancing their synaptic integration and boosting dentate output to promote antidepressant effects within hours.^[127] Recent studies highlight the hypersensitivity of semilunar granule cells—a specialized subset of dentate projection neurons—in epileptic contexts, where they exhibit heightened excitability and preferential activation during seizures, potentially amplifying aberrant network activity.^[128]

Effects of aging

Aging profoundly impacts granule cells across various brain regions, particularly through a marked decline in adult neurogenesis. In the human dentate gyrus, the production of new granule cells decreases with age, contributing to diminished hippocampal plasticity.^[129] Similarly, in the olfactory bulb, neurogenesis of granule cells shows an age-related impairment, though quantification is less precise; rodent models reveal a progressive reduction in the renewal of these interneurons, leading to fewer new cells integrating into the circuit and potentially underlying olfactory deficits in older individuals.^[130] This decline stems from reduced proliferation of neural stem cells in the subventricular zone and subgranular zone, independent of overt pathology.^[131] Morphological alterations in granule cells accompany this neurogenic fade, often manifesting as structural simplifications that impair connectivity. In the dentate gyrus, aging neurons exhibit shorter dendrites and reduced spine density, particularly in the inner molecular layer, which limits synaptic inputs and arborization complexity.^[132] These shifts reflect a broader trend of dendritic retraction and spine loss observed in aging neurons, reducing the surface area available for synaptic contacts.^[133] Functionally, these changes translate to diminished synaptic plasticity and adaptive capacity in granule cells. Aged dentate granule cells display impaired long-term potentiation and slower firing rate adaptation, hindering their role in pattern separation and memory encoding.^[134] In the olfactory bulb, reduced integration of new granule cells leads to weakened inhibitory modulation of mitral cells, contributing to sensory processing deficits. A 2025 study in Nature Neuroscience highlighted how aging causes mislocalization of splicing proteins like TDP-43 to the cytoplasm in neurons, which disrupts alternative splicing and destabilizes cellular stress responses, further exacerbating plasticity loss.^[115] Remaining granule cells may compensate with hyperexcitability, but this often fails to restore efficient circuit function.^[118] Underlying these effects are mechanisms such as telomere shortening and chronic low-grade inflammation, which accelerate cellular senescence in granule cells. Telomere attrition limits replicative potential in neural progenitors, while inflammation from microglial activation promotes oxidative stress and progenitor quiescence.^[135]^[136] These processes can be partially mitigated by lifestyle factors; for instance, lifelong aerobic exercise preserves granule cell integrity by enhancing neurogenesis rates, maintaining dendritic morphology, and supporting memory performance in aging rodents and humans.^[137]^[138] Such interventions highlight the potential for resilience against normative age-related declines in granule cell function.

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... cerebellum showed diffuse thinning of the molecular and granular layers with almost complete loss of Purkyně cells. Previous article in issue; Next article ...
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Dual roles of Aβ in proliferative processes in an amyloidogenic ...
Aug 30, 2017 · Our study showed that neurogenesis is impaired early on due to the remarkable diminution of SGZ progenitor cells (including type-1 and type-2 ...
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Oxidative stress and redox regulation on hippocampal-dependent ...
Reduced antioxidant capacity and exposure to low dose irradiation can significantly impede hippocampal-dependent functions of learning and memory.Missing: shortens | Show results with:shortens
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Impaired firing properties of dentate granule neurons in an ...
That these parameters were restored by PPARγ activation emphasizes the therapeutic value of RSG against early AD cognitive impairment. the dentate gyrus (DG) is ...
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Boosting Neurogenesis as a Strategy in Treating Alzheimer's Disease
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The Role of Hippocampal Mossy Fiber Sprouting in Epilepsy - NIH
Sep 26, 2019 · Sprouted mossy fibers serve as “spark plugs” that reliably activate (ie, detonate) recurrent excitatory networks within the dentate gyrus.
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Mossy Fiber Sprouting in the Dentate Gyrus - NCBI - NIH
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Inhibition of Granule Cell Dispersion and Seizure Development by ...
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Depression, Antidepressants, and Neurogenesis - PubMed Central
BDNF heterozygote mice show decreased rates of granule cell proliferation and survival, as well as loss of the upregulation of neurogenesis by exposure to ...
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Brain-Derived Neurotrophic Factor and Antidepressant Drugs Have ...
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Neurogenesis and generalization: a new approach to stratify ... - NIH
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Compensatory Regulation of Excitation/Inhibition Balance in ... - MDPI
This article explores the mechanisms underlying E/I balance regulation, focusing on the hippocampus in epilepsy and FXS, and emphasizing the possible ...
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Ketamine activates adult-born immature granule neurons to rapidly ...
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Human Hippocampal Neurogenesis Persists throughout Aging - NIH
Aging humans are thought to exhibit waning neurogenesis and exercise-induced angiogenesis, with a resulting volumetric decrease in the neurogenic hippocampal ...
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Age-related impairment of olfactory bulb neurogenesis in the ...
Taken together, results suggest that an age-related reduction in the renewal of OB granule cells may underlie the age-related smell impairment in DS.
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Aging Results in Reduced Epidermal Growth Factor Receptor ...
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Morphological changes among hippocampal dentate granule cells ...
We observed an increase in the thickness of the granule cell body layer, a decrease in the number of apical dendrite spines in the inner and outer molecular ...Missing: aging cerebellar
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The Ever-Changing Morphology of Hippocampal Granule Neurons ...
Type-1 cells have a triangular soma and a single apical prolongation that enters the granule cell layer, branching sparsely in the inner molecular layer, where ...
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Changes in the structural complexity of the aged brain - PMC
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Neural ageing and synaptic plasticity: prioritizing brain health in ...
Synaptic Plasticity impairments contribute to the processes of neural ageing. Targeting adaptive mechanisms in neural plasticity can help to attenuate age- ...
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Stress and telomere shortening: Insights from cellular mechanisms
A growing literature links stress to alterations in telomerase activity and telomere shortening across many species.
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Telomere attrition and inflammation: the chicken and the egg story
Aug 28, 2022 · This review focuses primarily on two mechanisms that have contributed to aging and associated pathologies: telomere attrition and inflammatory insults.
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The Neuroprotective Effects of Exercise: Maintaining a Healthy Brain ...
Oct 6, 2018 · Daily exercise improves memory, stimulates hippocampal neurogenesis and modulates immune and neuroimmune cytokines in aging rats. Brain ...
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Can physical exercise in old age improve memory and hippocampal ...
Physical exercise can convey a protective effect against cognitive decline in ageing and Alzheimer's disease. While the long-term health-promoting and ...