Mossy cells are large excitatory neurons located in the hilus of the dentate gyrus, representing approximately 5% of hilar neurons. These cells play critical roles in hippocampal circuit function, serving as a major source of feedback excitation to the dentate granule cell layer and contributing fundamentally to pattern separation, a computational process essential for distinguishing between similar memory representations 1. First characterized in detail during the 1980s and 1990s, mossy cells have emerged as increasingly important for understanding hippocampal function in both normal cognition and disease states.
The dentate gyrus serves as the gateway to the hippocampal formation, receiving input from the entorhinal cortex and relaying processed information to CA3. Within this circuit, mossy cells occupy a unique position: they receive direct input from granule cell mossy fibers (the axons of dentate granule neurons) and in turn provide extensive excitatory feedback to granule cells and interneurons throughout the dentate gyrus. This recurrent circuit position gives mossy cells substantial influence over dentate gyrus information processing.
Mossy cells have attracted particular attention due to their selective vulnerability in both Alzheimer's disease and temporal lobe epilepsy 2 3. The degeneration of mossy cells in these conditions contributes to characteristic memory deficits and circuit hyperexcitability, making them important therapeutic targets. Understanding mossy cell biology is therefore essential for developing treatments for these devastating neurological conditions.
Mossy cells reside in the hilus (also called the polymorphic layer) of the dentate gyrus, between the granule cell layer and the CA3 region. The hilus comprises the polymorphic layer of the dentate gyrus and contains diverse cell types, with mossy cells representing the largest excitatory population.
The morphology of mossy cells is distinctive and characteristic 4:
Cell Body: Mossy cells have large cell bodies measuring 15-20 μm in diameter, significantly larger than nearby interneurons. Their somata are typically ovoid or pyramidal in shape.
Dendrites: Mossy cells possess extensive dendritic trees that extend into both the molecular layer and the granule cell layer. The dendrites are covered with prominent spines called "thorny excrescences" that receive the majority of synaptic input from mossy fiber boutons. These large spines are a defining morphological feature.
Axonal Projections: Mossy cells have extensive axonal projections that constitute the major output pathway from the hilus. The axons project to:
The axonal projection pattern creates a feedback circuit whereby mossy cells receive input from granule cells and then send excitatory projections back togranule cells and to the molecular layer where they influence feedforward inhibition.
Within the hilus, mossy cells are distributed throughout but show certain regional preferences:
Spatial Distribution: Mossy cells are distributed relatively uniformly across the septotemporal (longitudinal) axis of the dentate gyrus, though slight variations in density may exist along this axis.
Layer Positioning: While primarily located in the polymorphic layer, mossy cell bodies can be found at various depths within the hilus, and some cells extend into the granule cell layer border.
Numbers: Estimates suggest that mossy cells constitute approximately 5% of the total neuronal population in the dentate gyrus hilus, with the remaining population consisting primarily of inhibitory interneurons.
Mossy cells can be identified by their expression of specific molecular markers:
Calretinin: One of the most reliable markers for mossy cells is the calcium-binding protein calretinin. Nearly all mossy cells express calretinin, making it useful for anatomical identification. However, calretinin is not exclusive to mossy cells, as some interneurons also express this protein 5.
Neuropeptide Y (NPY): Mossy cells express neuropeptide Y, which serves both as a marker and as a neuromodulator. NPY is co-released with glutamate from mossy cell terminals.
mGluR1 (GRM1): The metabotropic glutamate receptor subtype mGluR1 is expressed by mossy cells, where it contributes to synaptic plasticity and activity-dependent regulation.
Narp (NPTX2): Neuronal activity-regulated pentraxin (Narp) is expressed in mossy cells and contributes to excitatory synapse formation through its interaction with AMPA receptors 6.
Zif280 (EGR1): The immediate early gene Zif280 (also known as EGR1) is expressed in mossy cells and serves as an activity marker.
Recent single-cell transcriptomic studies have refined our understanding of mossy cell molecular identity 6:
Mossy cells receive synaptic input from multiple sources:
Mossy Fiber Input: The primary input to mossy cells comes from dentate granule cell axons (mossy fibers). Each mossy fiber makes multiple en passant synapses onto mossy cell thorny excrescences. This input is excitatory and uses glutamate as the neurotransmitter.
The mossy fiber to mossy cell connection is notable for:
Other Sources:
Mossy cells provide extensive excitatory output:
Granule Cell Feedback: Mossy cells project back to granule cells in the inner molecular layer, forming a major excitatory feedback pathway. This connection is thought to amplify dentate gyrus signaling.
Molecular Layer Interneurons: Mossy cells excite inhibitory interneurons in the molecular layer, which in turn provide feedforward inhibition to granule cells.
CA3 Projections: Mossy cells send projections to CA3, contributing to the trisynaptic circuit.
Local Collaterals: Mossy cell axon collaterals form excitatory connections with other mossy cells, creating a recurrent excitatory network within the hilus.
The mossy cell circuit performs several critical functions:
Feedback Excitation: Mossy cells provide positive feedback to granule cells, amplifying the signal that arrives from entorhinal cortex input. This amplification enhances the signal-to-noise ratio for relevant information.
Gain Control: Through their interactions with interneurons, mossy cells help control the gain of dentate gyrus transmission, modulating the flow of information to CA3.
Pattern Separation: By providing context-dependent modulation, mossy cells contribute to the pattern separation function of the dentate gyrus 7.
Mossy cells exhibit distinctive electrophysiological properties:
Firing Pattern: Mossy cells show regular spiking patterns with moderate firing rates. They can sustain high-frequency firing when activated.
Intrinsic Properties:
Active Properties:
Electrophysiological recordings from behaving animals have revealed:
Spatial Firing: Mossy cells show location-specific firing in the hilus, with firing fields that may relate to the animal's position in the environment.
Firing During Behavior: Mossy cells are most active during active exploration and during sharp-wave ripples, when hippocampal replay occurs.
Modulation by State: Mossy cell activity varies with behavioral state, being lower during sleep and higher during active wakefulness.
Pattern separation is the computational process by which similar inputs are transformed into distinct outputs, reducing interference between memory representations. The dentate gyrus performs this function, and mossy cells contribute critically:
Signal Amplification: The mossy cell feedback circuit amplifies differences between input patterns, enhancing separation.
Contextual Modulation: Mossy cells provide context-dependent modulation of granule cell outputs, helping to distinguish between similar inputs that occur in different contexts.
Recurrent Processing: The recurrent connections between mossy cells and granule cells enable iterative refinement of the separated patterns.
Studies support the essential role of mossy cells in pattern separation:
Lesion Studies: Selective lesions of mossy cells impair pattern separation performance in behavioral tasks.
Optogenetic Studies: Direct manipulation of mossy cell activity affects pattern separation ability 8.
Computational Models: Modeling studies demonstrate that mossy cells enhance the separation capacity of the dentate network.
The dentate gyrus continues to generate new neurons throughout life, and mossy cells play important roles in this process:
Synaptic Integration: Mossy cells form synapses with newborn granule cells as these neurons integrate into the circuit.
Activity-Dependent Maturation: Mossy cell activity influences the survival and maturation of new neurons.
Plasticity Regulation: The mossy cell to granule cell connection exhibits plasticity that may be important for encoding new memories.
Newborn neurons become integrated into the mossy cell circuit:
Mossy cells show early vulnerability in Alzheimer's disease, contributing to memory deficits:
Selective Loss: Studies in human AD brain tissue and animal models reveal selective degeneration of mossy cells early in disease progression 2.
Mechanisms: Multiple mechanisms may contribute to mossy cell vulnerability:
Mossy cell loss disrupts dentate gyrus circuit function:
Reduced Feedback Excitation: Loss of mossy cells reduces the excitatory feedback to granule cells, weakening dentate gyrus processing.
Impaired Pattern Separation: Mossy cell degeneration contributes to pattern separation deficits, a hallmark of early AD memory impairment.
Network Hypofunction: The overall result is reduced dentate gyrus output to CA3, contributing to hippocampal memory dysfunction 9.
Understanding mossy cell vulnerability suggests therapeutic approaches:
Neuroprotective Strategies: Protecting mossy cells from degeneration may preserve pattern separation function.
Circuit Repair: Mossy cell replacement or circuit restoration could potentially restore hippocampal function.
Targeted Interventions: Understanding the molecular mechanisms of mossy cell vulnerability may reveal novel therapeutic targets.
Mossy cells are selectively lost in temporal lobe epilepsy 3:
Early Death: Mossy cells are among the first neurons to die in the epileptic hippocampus, often before seizures manifest.
Mechanisms: Excitotoxicity from excessive mossy fiber activity likely contributes to mossy cell death, along with inflammatory processes.
Consequences: Mossy cell loss creates a self-perpetuating cycle that promotes further hyperexcitability.
Mossy cell loss contributes to epileptogenesis:
Loss of Feedback Inhibition: Mossy cells normally excite interneurons that provide feedback inhibition. Their loss disrupts this regulation.
Granule Cell Hyperexcitability: Without mossy cell-mediated regulation, granule cells become hyperexcitable.
Aberrant Sprouting: As mossy cells die, remaining neurons undergo axonal sprouting, forming abnormal recurrent connections 10.
Protecting or replacing mossy cells may help treat epilepsy:
Neuroprotective Approaches: Preventing mossy cell death could halt disease progression.
Circuit Modulation: Restoring mossy cell function through pharmacological or optogenetic approaches may normalize circuit function.
Mossy cells show age-related changes even in healthy aging:
These changes may contribute to age-related memory decline.
Mossy cells are vulnerable to traumatic brain injury:
Emerging evidence suggests mossy cell dysfunction in schizophrenia:
Mossy cells are studied using various techniques:
In Vivo Recording: Extracellular recordings from behaving animals reveal mossy cell firing properties and spatial coding.
In Vitro Slice Recording: Brain slice preparations allow detailed study of mossy cell synaptic properties and plasticity.
Optogenetic Identification: Cre-driver mouse lines allow optogenetic tagging of mossy cells for identification during recording.
Tracing Studies: Anterograde and retrograde tracers reveal mossy cell connectivity.
Immunohistochemistry: Antibodies against mossy cell markers enable anatomical visualization.
Electron Microscopy: Ultrastructural studies reveal synaptic specializations.
Single-Cell RNA Sequencing: Transcriptomic profiling reveals mossy cell subtypes and molecular properties 6.
Optogenetics: Channelrhodopsin expression allows precise control of mossy cell activity.
Chemogenetics: DREADDs enable long-term manipulation of mossy cell function.
Computational models have revealed mossy cell function:
Pattern Separation Models: Including mossy cells improves pattern separation in network models.
Memory Models: Mossy cells contribute to memory encoding and retrieval in computational models of hippocampal function.
Epilepsy Models: Mossy cell loss contributes to seizure-like dynamics in computational models.
Filter Theory: Mossy cells help the dentate gyrus filter incoming information, passing only salient patterns to CA3 11.
Computational Role: Theoretical analyses suggest mossy cells implement a "sparse distributed representation" that maximizes information storage capacity.
Mossy cells represent potential therapeutic targets:
Neuroprotective Agents: Compounds that protect mossy cells from degeneration could treat early AD and prevent epilepsy.
Modulatory Drugs: Drugs that enhance mossy cell function might improve pattern separation in aging or disease.
Anti-epileptic Strategies: Protecting mossy cells may prevent epileptogenesis.
Cell Replacement: Stem cell-derived mossy cells might eventually be used for circuit repair.
Gene Therapy: Targeting genes expressed in mossy cells could provide therapeutic benefit.
Brain-Machine Interfaces: Understanding mossy cell function may inform neural prosthetics.