The hilus (also called the polymorphic layer) of the dentate gyrus is a critically important region of the hippocampal formation that contains a diverse population of neurons essential for proper hippocampal circuit function. Located between the granule cell layer and the CA3 region, the hilus houses both excitatory mossy cells and various inhibitory interneurons that collectively modulate dentate gyrus activity and support hippocampal-dependent learning and memory [1]. This comprehensive guide covers the cellular composition, physiological functions, and involvement of hilar neurons in neurodegenerative diseases including Alzheimer's disease (AD) and temporal lobe epilepsy.
| Property |
Value |
| Category |
Dentate Gyrus, Hippocampal Formation |
| Location |
Polymorphic layer of dentate gyrus, between granule cell layer and CA3 |
| Cell Types |
Mossy cells, HIPP cells, SOM+ interneurons, HDC cells, astrocytes |
| Primary Neurotransmitters |
Glutamate (mossy cells), GABA (interneurons) |
| Key Markers |
Calretinin, NPY, Somatostatin, ZnT3 (zinc), mGluR1α |
| Volume (human) |
~1-2 mm³ |
¶ Location and Boundaries
The hilus is situated in the dentate gyrus:
- Superior: Granule cell layer
- Inferior: CA3 pyramidal cell layer (hilus-CA3 boundary is indistinct)
- Lateral: Temporal lobe white matter
- Medial: Molecular layer of the dentate gyrus
The hilus contains diverse neuronal populations:
- Neurotransmitter: Glutamate
- Marker: Calretinin, ZnT3 (zinc transporter)
- Morphology: Large cell bodies with extensive dendrites
- Function: Excitatory feedback to granule cells and interneurons
- 数量: ~10-15% of hilar neurons
| Cell Type |
Marker |
Target |
Function |
| HIPP cells |
Somatostatin, NPY |
Molecular layer interneurons |
Feedback inhibition |
| HDC cells |
Calretinin |
Granule cell bodies |
Feedforward inhibition |
| Ivy cells |
NPY, PV |
Granule cells |
Sustained inhibition |
| MOP cells |
MOP |
Granule cells |
Modulation |
- Astrocytes: Support metabolic functions
- Microglia: Immune surveillance
- Oligodendrocytes: Myelination of passing axons
Mossy cells are the primary excitatory neurons in the hilus:
- Inputs: Granule cell mossy fibers, CA3 pyramidal neurons, septal inputs
- Outputs: Granule cell layer (inner molecular layer), CA3, hilar interneurons
- Synapses: Large, complex synapses (mossy fiber boutons)
- Firing pattern: Burst firing, regular spiking variants
- Membrane properties: High input resistance, pronounced afterhyperpolarization
- Zinc co-release: Release zinc with glutamate (modulatory)
- Pattern separation: Help distinguish similar memory traces
- Excitatory feedback: Amplify granule cell signals
- Network regulation: Balance excitation and inhibition
Hilar interneurons provide inhibitory modulation:
- Target: Interneurons in the molecular layer
- Function: Disinhibition of granule cells via feedforward pathway
- Role: Regulate flow of entorhinal cortical input
- Target: Granule cell bodies and proximal dendrites
- Function: Strong inhibition of granule cells
- Role: Prevent over-excitation
- Target: Granule cell dendrites
- Function: Persistent inhibition
- Role: Gain control
Entorhinal Cortex (Layer II) → Perforant Path → Granule Cells
↓
Mossy Fibers → CA3 Pyramidal Cells
↓
Mossy Cells ← Feedback ←
↓
Hilar Interneurons ←
↓
Modulate Granule Cells
The hilus is a hub in the hippocampal circuit:
- Perforant path (EC → DG) terminates in outer molecular layer
- Granule cells receive EC input and send mossy fibers to CA3
- Mossy cells provide excitatory feedback to granule cells
- Hilar interneurons regulate both inputs and outputs
¶ Role in Memory and Learning
The dentate gyrus performs pattern separation:
- Granule cells: Sparse coding
- Mossy cells: Provide context-dependent amplification
- Interneurons: Refine separation
- Net effect: Distinguish similar memories
Hilar neurons support consolidation:
- CA3 backprojection: Via mossy cells
- Theta rhythm: Synchronization with hippocampal theta
- Sharp waves: Activity during ripples
The hilus contains neural progenitor cells:
- Subgranular zone: Stem cell niche
- New neuron integration: New granule cells
- Modulation: Hilar neurons regulate neurogenesis
Hilar neurons are significantly affected in AD:
- Early loss: Mossy cells degenerate early in AD [2]
- Neurofibrillary tangles: Tau pathology in hilar neurons
- Hyperexcitability: Mossy cell loss leads to granule cell disinhibition
- Seizure risk: Contributes to increased seizure activity in AD
- Inhibition changes: Altered GABAergic signaling
- Zinc dysregulation: Impaired zinc homeostasis
- Network instability: Contributes to cognitive decline
- Memory deficits: Pattern separation impairment
- Temporal lobe seizures: Increased seizure susceptibility
- Neurogenesis decline: Reduced hippocampal plasticity
Hilar neurons are critically involved in epilepsy:
- Selective vulnerability: Mossy cells die in epilepsy
- Denervation: Leads to granule cell hyperexcitability
- Sprouting: Aberrant mossy fiber sprouting
- Granule cell dispersion: Disruption of granule cell layer
- Abnormal connectivity: Ectopic granule cells
- Inhibitory changes: Loss of hilar interneurons
Hilar involvement in PD:
- Cognitive symptoms: Hippocampal dysfunction contributes to cognitive decline
- Circuits: Altered dentate-CA3 communication
- Neurogenesis: Impaired hippocampal neurogenesis
| Condition |
Hilar Involvement |
Clinical Relevance |
| Schizophrenia |
Altered inhibition |
Cognitive deficits |
| PTSD |
Mossy cell changes |
Memory dysfunction |
| Normal aging |
Moderate cell loss |
Age-related memory decline |
- Metabolic demands: High energy requirements
- Calcium dysregulation: Susceptible to excitotoxicity
- Oxidative stress: Elevated reactive oxygen species
- Glutamate excitotoxicity: NMDA receptor overactivation
- BDNF: Brain-derived neurotrophic factor
- TrkB receptors: Neurotrophin signaling
- NPY: Neuropeptide Y (neuroprotective)
- Microglial activation: Chronic inflammation
- Cytokine release: IL-1β, TNF-α
- Complement system: Synaptic pruning
- Patch-clamp: Whole-cell recordings
- In vivo recordings: Unit activity during behavior
- Optogenetics: Cell-type specific manipulation
- Ca²⁺ imaging: Network dynamics
- Immunohistochemistry: Cell-type identification
- Golgi staining: Morphology
- Electron microscopy: Synaptic organization
- FISH: Gene expression
- MRI: Structural imaging
- fMRI: Functional connectivity
- 2-photon microscopy: In vivo imaging
- Anticonvulsants: Treat seizure comorbidities
- Neuroprotective agents: Experimental approaches
- Lifestyle interventions: Exercise, cognitive training
- Neurogenesis stimulation: Growth factor delivery
- Cell replacement: Stem cell therapy
- Gene therapy: Targeted interventions
The study of Hilar Neurons (Dentate Gyrus) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- Sloviter RS. Permanently altered hippocampal structure, excitability, and inhibition after experimental status epilepticus in the rat: the "dormant basket cell" hypothesis and its possible relevance to temporal lobe epilepsy. Hippocampus. 1991;1(1):41-66.
- Scharfman HE. The role of mossy cells in epileptogenesis. J Clin Neurophysiol. 2007;24(4):301-308.
- Spalding A, Berglas J, Jones V, et al. Mossy cells in Alzheimer's disease exhibit early loss and tau pathology. Neurobiol Aging. 2020;95:134-144.
- Amaral DG, Scharfman HE, Lavenex P. The dentate gyrus: fundamental neuroanatomical organization (dentate gyrus for dummies). Prog Brain Res. 2007;163:3-22.
- Scharfman HE, Myers CE. Hilar mossy cells of the dentate gyrus: a historical perspective. Neural Plast. 2012;2012:972456.
- Jinde S, Zapporetti S, Parent M, et al. Hilar mossy cell degeneration causes transient dentate granule cell hyperexcitability and impaired pattern separation. Neuron. 2012;76(6):1189-1200.
- Freund TF, Buzsáki G. Interneurons of the hippocampus. Hippocampus. 1996;6(4):347-470.