Cerebellar granule cell

Last updated

Cerebellar granule cell
Parallel-fibers.png
Granule cells, parallel fibers, and flattened dendritic trees of Purkinje cells
Details
Location Cerebellum
Shapesmall cell with few dendrites
Functionexcitatory
Neurotransmitter glutamate
Presynaptic connections Mossy fibers and Golgi cells
Postsynaptic connectionsParallel fibers to cerebellar cortex
Anatomical terms of neuroanatomy

Cerebellar granule cells form the thick granular layer of the cerebellar cortex and are among the smallest neurons in the brain. (The term granule cell is used for several unrelated types of small neurons in various parts of the brain.) Cerebellar granule cells are also the most numerous neurons in the brain: in humans, estimates of their total number average around 50 billion, which means that they constitute about 3/4 of the brain's neurons. [1]

Contents

Structure

The cell bodies are packed into a thick granular layer at the bottom of the cerebellar cortex. A granule cell emits only four to five dendrites, each of which ends in an enlargement called a dendritic claw. [1] These enlargements are sites of excitatory input from mossy fibers and inhibitory input from Golgi cells.

The thin, unmyelinated axons of granule cells rise vertically to the upper (molecular) layer of the cortex, where they split in two, with each branch traveling horizontally to form a parallel fiber; the splitting of the vertical branch into two horizontal branches gives rise to a distinctive "T" shape. A parallel fiber runs for an average of 3 mm in each direction from the split, for a total length of about 6 mm (about 1/10 of the total width of the cortical layer). [1] As they run along, the parallel fibers pass through the dendritic trees of Purkinje cells, contacting one of every 3–5 that they pass, making a total of 80–100 synaptic connections with Purkinje cell dendritic spines. [1] Granule cells use glutamate as their neurotransmitter, and therefore exert excitatory effects on their targets.

Development

In normal development, endogenous Sonic hedgehog signaling stimulates rapid proliferation of cerebellar granule neuron progenitors (CGNPs) in the external granule layer (EGL). Cerebellum development occurs during late embryogenesis and the early postnatal period, with CGNP proliferation in the EGL peaking during early development (P7, postnatal day 7, in the mouse). [2] As CGNPs terminally differentiate into cerebellum granule cells (also called cerebellar granule neurons, CGNs), they migrate to the internal granule layer (IGL), forming the mature cerebellum (by P20, post-natal day 20 in the mouse). [2] Mutations that abnormally activate Sonic hedgehog signaling predispose to cancer of the cerebellum (medulloblastoma) in humans with Gorlin syndrome and in genetically engineered mouse models. [3] [4]

Function

Granule cells receive all of their input from mossy fibers, but outnumber them 200 to 1 (in humans). Thus, the information in the granule cell population activity state is the same as the information in the mossy fibers, but recoded in a much more expansive way. Because granule cells are so small and so densely packed, it has been very difficult to record their spike activity in behaving animals, so there is little data to use as a basis of theorizing. The most popular concept of their function was proposed by David Marr, who suggested that they could encode combinations of mossy fiber inputs. The idea is that with each granule cell receiving input from only 4–5 mossy fibers, a granule cell would not respond if only a single one of its inputs was active, but would respond if more than one were active. This "combinatorial coding" scheme would potentially allow the cerebellum to make much finer distinctions between input patterns than the mossy fibers alone would permit. [5]

3D genome architecture

Cerebellar granule cells acquire a characteristic genome architecture: ultra-long-range intrachromosomal contacts (10-100Mb), specific interchromosomal contacts and restructuring of active/inactive chromatin compartmentalisation (scA/B) throughout life. This genomic dynamic is modulated by cell type-specific genes, but not by CpG methylation at the global level and could be a cellular strategy to manage space and energy. [6]

All these features have been observed in murine and human cerebellar tissues, so the mouse model seems to be a good animal model to study the genome structure of cerebellar granule cells, despite the difference in lifespan between the two types of organisms. [6]

Role in disease

In neurodevelopmental disorders, including autism spectrum disorders (ASD), alterations in the chromatin remodelling of granule cells have been identified. This is due to mutations in genes encoding proteins involved in chromatin remodelling. One of these genes is CHD4. [7]

CHD4 is a protein that modulates synaptogenesis between granule cells and Purkinje cells through chromatin remodelling (specifically, it suppresses genomic accessibility). Mutations in it lead to alterations in synaptogenesis, as a consequence of increased accessibility to genome-wide promoters and enhancers (which are repressed under physiological developmental conditions). [8] However, these alterations at the chromatin level have no effect on the 3D genome architecture of cerebellar granule cells. [6]

Related Research Articles

<span class="mw-page-title-main">Cerebellum</span> Structure at the rear of the vertebrate brain, beneath the cerebrum

The cerebellum is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as it or even larger. In humans, the cerebellum plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language as well as emotional control such as regulating fear and pleasure responses, but its movement-related functions are the most solidly established. The human cerebellum does not initiate movement, but contributes to coordination, precision, and accurate timing: it receives input from sensory systems of the spinal cord and from other parts of the brain, and integrates these inputs to fine-tune motor activity. Cerebellar damage produces disorders in fine movement, equilibrium, posture, and motor learning in humans.

<span class="mw-page-title-main">Neural pathway</span> Connection formed between neurons that allows neurotransmission

In neuroanatomy, a neural pathway is the connection formed by axons that project from neurons to make synapses onto neurons in another location, to enable neurotransmission. Neurons are connected by a single axon, or by a bundle of axons known as a nerve tract, or fasciculus. Shorter neural pathways are found within grey matter in the brain, whereas longer projections, made up of myelinated axons, constitute white matter.

<span class="mw-page-title-main">Pyramidal cell</span> Projection neurons in the cerebral cortex and hippocampus

Pyramidal cells, or pyramidal neurons, are a type of multipolar neuron found in areas of the brain including the cerebral cortex, the hippocampus, and the amygdala. Pyramidal cells are the primary excitation units of the mammalian prefrontal cortex and the corticospinal tract. Pyramidal neurons are also one of two cell types where the characteristic sign, Negri bodies, are found in post-mortem rabies infection. Pyramidal neurons were first discovered and studied by Santiago Ramón y Cajal. Since then, studies on pyramidal neurons have focused on topics ranging from neuroplasticity to cognition.

Synaptogenesis is the formation of synapses between neurons in the nervous system. Although it occurs throughout a healthy person's lifespan, an explosion of synapse formation occurs during early brain development, known as exuberant synaptogenesis. Synaptogenesis is particularly important during an individual's critical period, during which there is a certain degree of synaptic pruning due to competition for neural growth factors by neurons and synapses. Processes that are not used, or inhibited during their critical period will fail to develop normally later on in life.

<span class="mw-page-title-main">Basket cell</span>

Basket cells are inhibitory GABAergic interneurons of the brain, found throughout different regions of the cortex and cerebellum.

<span class="mw-page-title-main">Climbing fiber</span> Series of neuronal projections from the inferior olivary nucleus located in the medulla oblongata

Climbing fibers are the name given to a series of neuronal projections from the inferior olivary nucleus located in the medulla oblongata.

<span class="mw-page-title-main">Purkinje cell</span> Specialized neuron in the cerebellum

Purkinje cells or Purkinje neurons, named for Czech physiologist Jan Evangelista Purkyně who identified them in 1837, are a unique type of prominent large neurons located in the cerebellar cortex of the brain. With their flask-shaped cell bodies, many branching dendrites, and a single long axon, these cells are essential for controlling motor activity. Purkinje cells mainly release GABA neurotransmitter, which inhibits some neurons to reduce nerve impulse transmission. Purkinje cells efficiently control and coordinate the body's motor motions through these inhibitory actions.

An apical dendrite is a dendrite that emerges from the apex of a pyramidal cell. Apical dendrites are one of two primary categories of dendrites, and they distinguish the pyramidal cells from spiny stellate cells in the cortices. Pyramidal cells are found in the prefrontal cortex, the hippocampus, the entorhinal cortex, the olfactory cortex, and other areas. Dendrite arbors formed by apical dendrites are the means by which synaptic inputs into a cell are integrated. The apical dendrites in these regions contribute significantly to memory, learning, and sensory associations by modulating the excitatory and inhibitory signals received by the pyramidal cells.

<span class="mw-page-title-main">Stellate cell</span>

Stellate cells are neurons in the central nervous system, named for their star-like shape formed by dendritic processes radiating from the cell body. Many stellate cells are GABAergic and are located in the molecular layer of the cerebellum. Stellate cells are derived from dividing progenitor cells in the white matter of postnatal cerebellum. Dendritic trees can vary between neurons. There are two types of dendritic trees in the cerebral cortex, which include pyramidal cells, which are pyramid shaped and stellate cells which are star shaped. Dendrites can also aid neuron classification. Dendrites with spines are classified as spiny, those without spines are classified as aspinous. Stellate cells can be spiny or aspinous, while pyramidal cells are always spiny. Most common stellate cells are the inhibitory interneurons found within the upper half of the molecular layer in the cerebellum. Cerebellar stellate cells synapse onto the dendritic trees of Purkinje cells and send inhibitory signals. Stellate neurons are sometimes found in other locations in the central nervous system; cortical spiny stellate cells are found in layer IVC of the primary visual cortex. In the somatosensory barrel cortex of mice and rats, glutamatergic (excitatory) spiny stellate cells are organized in the barrels of layer 4. They receive excitatory synaptic fibres from the thalamus and process feed forward excitation to 2/3 layer of the primary visual cortex to pyramidal cells. Cortical spiny stellate cells have a 'regular' firing pattern. Stellate cells are chromophobes, that is cells that does not stain readily, and thus appears relatively pale under the microscope.

<span class="mw-page-title-main">Golgi cell</span>

In neuroscience, Golgi cells are the most abundant inhibitory interneurons found within the granular layer of the cerebellum. Golgi cells can be found in the granular layer at various layers. The Golgi cell is essential for controlling the activity of the granular layer. They were first identified as inhibitory in 1964. It was also the first example of an inhibitory feedback network in which the inhibitory interneuron was identified anatomically. Golgi cells produce a wide lateral inhibition that reaches beyond the afferent synaptic field and inhibit granule cells via feedforward and feedback inhibitory loops. These cells synapse onto the dendrite of granule cells and unipolar brush cells. They receive excitatory input from mossy fibres, also synapsing on granule cells, and parallel fibers, which are long granule cell axons. Thereby this circuitry allows for feed-forward and feed-back inhibition of granule cells.

<span class="mw-page-title-main">Reeler</span> Mouse mutant

A reeler is a mouse mutant, so named because of its characteristic "reeling" gait. This is caused by the profound underdevelopment of the mouse's cerebellum, a segment of the brain responsible for locomotion. The mutation is autosomal and recessive, and prevents the typical cerebellar folia from forming.

<span class="mw-page-title-main">Mossy fiber (hippocampus)</span> Pathway in the hippocampus

In the hippocampus, the mossy fiber pathway consists of unmyelinated axons projecting from granule cells in the dentate gyrus that terminate on modulatory hilar mossy cells and in Cornu Ammonis area 3 (CA3), a region involved in encoding short-term memory. These axons were first described as mossy fibers by Santiago Ramón y Cajal as they displayed varicosities along their lengths that gave them a mossy appearance. The axons that make up the pathway emerge from the basal portions of the granule cells and pass through the hilus of the dentate gyrus before entering the stratum lucidum of CA3. Granule cell synapses tend to be glutamatergic, though immunohistological data has indicated that some synapses contain neuropeptidergic elements including opiate peptides such as dynorphin and enkephalin. There is also evidence for co-localization of both GABAergic and glutamatergic neurotransmitters within mossy fiber terminals. GABAergic and glutamatergic co-localization in mossy fiber boutons has been observed primarily in the developing hippocampus, but in adulthood, evidence suggests that mossy fiber synapses may alternate which neurotransmitter is released through activity-dependent regulation.

<span class="mw-page-title-main">Mossy fiber (cerebellum)</span> Major input to cerebellum

Mossy fibers are one of the major inputs to cerebellum. There are many sources of this pathway, the largest of which is the cerebral cortex, which sends input to the cerebellum via the pontocerebellar pathway. Other contributors include the vestibular nerve and nuclei, the spinal cord, the reticular formation, and feedback from deep cerebellar nuclei. Axons enter the cerebellum via the middle and inferior cerebellar peduncles, where some branch to make contact with deep cerebellar nuclei. They ascend into the white matter of the cerebellum, where each axon branches to innervate granule cells in several cerebellar folia.

<span class="mw-page-title-main">Anatomy of the cerebellum</span> Structures in the cerebellum, a part of the brain

The anatomy of the cerebellum can be viewed at three levels. At the level of gross anatomy, the cerebellum consists of a tightly folded and crumpled layer of cortex, with white matter underneath, several deep nuclei embedded in the white matter, and a fluid-filled ventricle in the middle. At the intermediate level, the cerebellum and its auxiliary structures can be broken down into several hundred or thousand independently functioning modules or compartments known as microzones. At the microscopic level, each module consists of the same small set of neuronal elements, laid out with a highly stereotyped geometry.

<span class="mw-page-title-main">Granule cell</span> Type of neuron with a very small cell body

The name granule cell has been used for a number of different types of neurons whose only common feature is that they all have very small cell bodies. Granule cells are found within the granular layer of the cerebellum, the dentate gyrus of the hippocampus, the superficial layer of the dorsal cochlear nucleus, the olfactory bulb, and the cerebral cortex.

<span class="mw-page-title-main">Rhombic lip</span> Posterior section of the developing metencephalon

The rhombic lip is a posterior section of the developing metencephalon which can be recognized transiently within the vertebrate embryo. It extends posteriorly from the roof of the fourth ventricle to dorsal neuroepithelial cells. The rhombic lip can be divided into eight structural units based on rhombomeres 1-8 (r1-r8), which can be recognized at early stages of hindbrain development. Producing granule cells and five brainstem nuclei, the rhombic lip plays an important role in developing a complex cerebellar neural system.

<span class="mw-page-title-main">Unipolar brush cell</span>

Unipolar brush cells (UBCs) are a class of excitatory glutamatergic interneuron found in the granular layer of the cerebellar cortex and also in the granule cell domain of the cochlear nucleus.

<span class="mw-page-title-main">Hippocampus proper</span> Part of the brain of mammals

The hippocampus proper refers to the actual structure of the hippocampus which is made up of three regions or subfields. The subfields CA1, CA2, and CA3 use the initials of cornu Ammonis, an earlier name of the hippocampus.

<span class="mw-page-title-main">AGTPBP1 (gene)</span> Human protein-coding gene

ATP/GTP binding protein 1 is gene that encodes the protein known as cytosolic carboxypeptidase 1 (CCP1), originally named NNA1. Mice with a naturally occurring mutation of the Agtpbp1 gene are known as pcd mice.

An axo-axonic synapse is a type of synapse, formed by one neuron projecting its axon terminals onto another neuron's axon.

References

  1. 1 2 3 4 Llinas RR, Walton KD, Lang EJ (2004). "Ch. 7 Cerebellum". In Shepherd GM (ed.). The Synaptic Organization of the Brain. New York: Oxford University Press. ISBN   978-0-19-515955-4.
  2. 1 2 Hatten, M (1995). "Mechanisms of neural patterning and specification in the developing cerebellum". Annu Rev Neurosci. 18: 385–408. doi:10.1146/annurev.ne.18.030195.002125. PMID   7605067.
  3. Roussel, M (2011). Cerebellum development and medulloblastoma. Current Topics in Developmental Biology. Vol. 94. pp. 235–82. doi:10.1016/B978-0-12-380916-2.00008-5. ISBN   9780123809162. PMC   3213765 . PMID   21295689.{{cite book}}: |journal= ignored (help)
  4. Polkinghorn, W (2007). "Medulloblastoma: tumorigenesis, current clinical paradigm, and efforts to improve risk stratification". Nat Clin Pract Oncol. 4 (5): 295–304. doi:10.1038/ncponc0794. PMID   17464337. S2CID   24461280.
  5. Marr D (1969). "A theory of cerebellar cortex". J. Physiol. 202 (2): 437–70. doi:10.1113/jphysiol.1969.sp008820. PMC   1351491 . PMID   5784296.
  6. 1 2 3 Tan, L., Shi, J., Moghadami, S., Parasar, B., Wright, C. P., Seo, Y., et al. (2023). «Lifelong restructuring of 3D genome architecture in cerebellar granule cells.Science (American Association for the Advancement of Science), 381(6662), 1112-1119. doi:10.1126/science.adh325». https://www.science.org/doi/10.1126/science.adh3253
  7. Legüe, Marcela (2022). "Relevancia de los mecanismos epigenéticos en el neurodesarrollo normal y consecuencias de sus perturbaciones | Revista Médica Clínica Las Condes". www.elsevier.es. Retrieved January 16, 2024.
  8. Goodman, Jared V.; Yamada, Tomoko; Yang, Yue; Kong, Lingchun; Wu, Dennis Y.; Zhao, Guoyan; Gabel, Harrison W.; Bonni, Azad (July 9, 2020). "The chromatin remodeling enzyme Chd4 regulates genome architecture in the mouse brain". Nature Communications. 11 (1): 3419. doi:10.1038/s41467-020-17065-z. ISSN   2041-1723. PMC   7347877 .