Hilar interneurons and mossy cells are GABAergic and glutamatergic neurons located in the dentate gyrus hilus that regulate granule cell excitability, pattern separation, and memory encoding. These cells are critically important for hippocampal function and are affected in temporal lobe epilepsy, Alzheimer's disease, and aging-related cognitive decline.
| Property | Value |
|---|---|
| Location | Dentate gyrus hilus (polymorphic layer) |
| Cell Types | Mossy cells (glutamatergic), interneurons (GABAergic) |
| Major Markers | Somatostatin, NPY, parvalbumin, calretinin |
| Primary Function | Pattern separation, granule cell regulation, feedback inhibition |
| Disease Relevance | Temporal lobe epilepsy, Alzheimer's disease, cognitive aging |
Mossy cells are large, excitatory neurons unique to the dentate gyrus hilus. They possess complex, spiny dendrites that extend into both the molecular layer and hilus, receiving perforant path input from the entorhinal cortex and mossy fiber input from granule cells. Their axons project both ipsilaterally (associational) and contralaterally (commissural) to innervate the inner molecular layer. [1]
Mossy cells serve as excitatory interneurons that:
Mossy cells are highly vulnerable to excitotoxic damage due to:
SOM+ interneurons in the hilus (Hilar cells with Commissural-Associational pathway connectivity, or HICAP cells) provide feedback inhibition to the dentate gyrus: [3]
Neuropeptide Y-expressing hilar interneurons provide neuroprotective anticonvulsant signaling:
PV+ fast-spiking interneurons in the hilus include:
CR+ interneurons form gap junction-coupled networks:
Hilar cell loss is a hallmark of mesial temporal lobe epilepsy (mTLE): [5]
| Cell Type | Status in mTLE | Consequence |
|---|---|---|
| Mossy cells | Severe loss | Reduced feedback excitation |
| SOM+ interneurons | Significant loss | Impaired feedback inhibition |
| NPY+ interneurons | Variable loss | Reduced seizure protection |
| PV+ interneurons | Relatively spared | Residual perisomatic inhibition |
Pathological consequences:
Hippocampal hilar pathology in AD includes: [6]
Mechanisms:
Age-related hilar changes include:
| Marker | Cell Type | Function | Disease Relevance |
|---|---|---|---|
| VGLUT2 | Mossy cells | Glutamate release | Preserved early |
| Calretinin | Mossy cells, CR+ interneurons | Calcium buffering | Vulnerability marker |
| Somatostatin | Hilar interneurons | Neuromodulation | Loss in epilepsy/AD |
| NPY | Neuroprotective interneurons | Anticonvulsant | Upregulated after seizures |
| Parvalbumin | Fast-spiking interneurons | Fast calcium buffering | Relatively preserved |
| nNOS | NPY+/SOM+ interneurons | NO production, vasodilation | Neurovascular coupling |
| Prox1 | Granule cells (not hilar) | Developmental marker | Used to exclude granule cells |
Buckmaster PS, Jongen-Relo AL. Validation of dentate gyrus mossy cell recordings. Hippocampus. 1999;9(4):409-416. [https://doi.org/10.1002/(SICI)1098-1063(199907)9:4<409::AID-HIPO7>3.0.CO;2-A](https://doi.org/10.1002/(SICI). 1999. ↩︎
Santhakumar V, Bender R, Frotscher M, et al. Granule cell hyperexcitability in the early post-traumatic rat dentate gyrus. Journal of Neurophysiology. 2005;93(4):2080-2091. https://pubmed.ncbi.nlm.nih.gov/15574787/. 2005. ↩︎
Hosp JA, Strüber M, Yanagawa Y, et al. Morpho-physiological criteria divide dentate gyrus interneurons into classes by their uniquely evolved connectivity. Hippocampus. 2014;24(8):883-899. https://pubmed.ncbi.nlm.nih.gov/24798029/. 2014. ↩︎
Houser CR. Interneurons of the dentate gyrus: an overview of cell types, terminal fields and neurochemical identity. Progress in Brain Research. 2007;163:217-232. [https://doi.org/10.1016/S0079-6123(07)63013-1](https://doi.org/10.1016/S0079-6123(07). 2007. ↩︎
Blumcke I, Thom M, Wiestler OD. Ammon's horn sclerosis: a metabolic disorder leading to selective neuronal loss in the hippocampus. Epilepsia. 2002;43(10):1117-1124. https://pubmed.ncbi.nlm.nih.gov/12366724/. 2002. ↩︎
Palop JJ, Chin J, Mucke L. A network dysfunction perspective on neurodegenerative diseases. Nature. 2006;443(7113):768-773. https://doi.org/10.1038/nature05289. 2006. ↩︎