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Purkinje cells, or Purkinje neurons, are a class of
GABAergic In molecular biology and physiology, something is GABAergic or GABAnergic if it pertains to or affects the neurotransmitter GABA. For example, a synapse is GABAergic if it uses GABA as its neurotransmitter, and a GABAergic neuron produces GABA. A ...
inhibitory
neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...
s located in the
cerebellum The cerebellum (Latin for "little brain") 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 or even larger. In humans, the cerebe ...
. They are named after their discoverer, Czech
anatomist Anatomy () is the branch of biology concerned with the study of the structure of organisms and their parts. Anatomy is a branch of natural science that deals with the structural organization of living things. It is an old science, having it ...
Jan Evangelista Purkyně, who characterized the cells in 1839.


Structure

These
cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...
are some of the largest
neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...
s in the human
brain A brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as Visual perception, vision. I ...
( Betz cells being the largest), with an intricately elaborate
dendritic Dendrite derives from the Greek word "dendron" meaning ( "tree-like"), and may refer to: Biology *Dendrite, a branched projection of a neuron * Dendrite (non-neuronal), branching projections of certain skin cells and immune cells Physical *Dendr ...
arbor, characterized by a large number of dendritic spines. Purkinje cells are found within the Purkinje layer in the
cerebellum The cerebellum (Latin for "little brain") 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 or even larger. In humans, the cerebe ...
. Purkinje cells are aligned like
domino Dominoes is a family of tile-based games played with gaming pieces, commonly known as dominoes. Each domino is a rectangular tile, usually with a line dividing its face into two square ''ends''. Each end is marked with a number of spots (also c ...
s stacked one in front of the other. Their large dendritic arbors form nearly
two-dimensional In mathematics, a plane is a Euclidean ( flat), two-dimensional surface that extends indefinitely. A plane is the two-dimensional analogue of a point (zero dimensions), a line (one dimension) and three-dimensional space. Planes can arise as ...
layers through which
parallel fiber Parallel is a geometric term of location which may refer to: Computing * Parallel algorithm * Parallel computing * Parallel metaheuristic * Parallel (software), a UNIX utility for running programs in parallel * Parallel Sysplex, a cluster of ...
s from the deeper-layers pass. These parallel fibers make relatively weaker excitatory (
glutamatergic Glutamatergic means "related to glutamate". A glutamatergic agent (or drug) is a chemical that directly modulates the excitatory amino acid (glutamate/aspartate) system in the body or brain. Examples include excitatory amino acid receptor agonis ...
) synapses to spines in the Purkinje cell dendrite, whereas
climbing fibers Climbing fibers are the name given to a series of neuronal projections from the inferior olivary nucleus located in the medulla oblongata. These axons pass through the pons and enter the cerebellum via the inferior cerebellar peduncle wher ...
originating from the inferior olivary nucleus in the medulla provide very powerful excitatory input to the proximal dendrites and cell soma. Parallel fibers pass
orthogonal In mathematics, orthogonality is the generalization of the geometric notion of '' perpendicularity''. By extension, orthogonality is also used to refer to the separation of specific features of a system. The term also has specialized meanings in ...
ly through the Purkinje neuron's dendritic arbor, with up to 200,000 parallel fibers forming a Granule-cell-Purkinje-cell synapse with a single Purkinje cell. Each Purkinje cell receives approximately 500 climbing fiber synapses, all originating from a single climbing fiber. Both basket and stellate cells (found in the cerebellar molecular layer) provide inhibitory (GABAergic) input to the Purkinje cell, with basket cells synapsing on the Purkinje cell axon initial segment and stellate cells onto the dendrites. Purkinje cells send inhibitory projections to the deep cerebellar nuclei, and constitute the sole output of all
motor coordination Motor coordination is the orchestrated movement of multiple body parts as required to accomplish intended actions, like walking. This coordination is achieved by adjusting kinematic and kinetic parameters associated with each body part involved in ...
in the cerebellar cortex.


Molecular

The Purkinje layer of the cerebellum, which contains the cell bodies of the Purkinje cells and Bergmann glia, express a large number of unique genes. Purkinje-specific gene markers were also proposed by comparing the transcriptome of Purkinje-deficient mice with that of wild-type mice. One illustrative example is the Purkinje cell protein 4 ( PCP4) in
knockout mice A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
, which exhibit impaired locomotor learning and markedly altered
synaptic plasticity In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. Since memories are postulated to be represented by vastly interconnected neural circuits ...
in Purkinje neurons. PCP4 accelerates both the association and dissociation of
calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar ...
(Ca2+) with
calmodulin Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. It is an intracellular target of the secondary messenger Ca2+, and the bin ...
(CaM) in the cytoplasm of Purkinje cells, and its absence impairs the physiology of these neurons.


Development

Mammalian embryonic research has detailed the neurogenic origins of Purkinje cells. During early development Purkinje cells arise in the ventricular zone in the neural tube, the nervous system´s precursor in the embryo. All cerebellar neurons derive from germinal neuroepithelia from the ventricular zone. Purkinje cells are specifically generated from progenitors in the ventricular neuroepithelium of the embryonic cerebellar primordium. The first cells generated from the cerebellar primordium form a cap over a diamond-shaped cavity of the developing brain called the fourth ventricle forming the two cerebellar hemispheres. The Purkinje cells that develop later are those of the cerebellum's center-lying section called the vermis. They develop in the cerebellar primordium that covers the fourth ventricle and below a fissure-like region called the isthmus of the developing brain. Purkinje cells migrate toward the outer surface of the cerebellar cortex and form the Purkinje cell layer. Purkinje cells are born during the earliest stages of cerebellar neurogenesis. Neurogenin2, together with neurogenin1, are transiently expressed in restricted domains of the ventricular neuroepithelium during the time-window of Purkinje cell genesis. This spatio-temporal distribution pattern suggests that neurogenins are involved in the specification of phenotypically heterogeneous Purkinje cell subsets, ultimately responsible for constructing the framework of the cerebellar topography. There is evidence in mice and humans that
bone marrow Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...
cells either fuse with or generate cerebellar Purkinje cells, and it is possible that bone marrow cells, either by direct generation or by cell fusion, could play a role in repair of central nervous system damage. Further evidence points yet towards the possibility of a common
stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of ...
ancestor among Purkinje neurons,
B-lymphocytes B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted o ...
and
aldosterone Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays a c ...
-producing
cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...
of the human
adrenal cortex The adrenal cortex is the outer region and also the largest part of an adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. It is ...
.


Function

Purkinje cells show two distinct forms of electrophysiological activity: * Simple spikes occur at rates of 17 – 150 Hz (Raman and Bean, 1999), either spontaneously or when Purkinje cells are activated synaptically by the parallel fibers, the axons of the granule cells. * Complex spikes are slow, 1–3 Hz spikes, characterized by an initial prolonged large-amplitude spike, followed by a high-frequency burst of smaller-amplitude action potentials. They are caused by climbing fiber activation and can involve the generation of calcium-mediated action potentials in the dendrites. Following complex spike activity, simple spikes can be suppressed by the powerful complex spike input. Purkinje cells show spontaneous electrophysiological activity in the form of trains of spikes both sodium-dependent and calcium-dependent. This was initially shown by
Rodolfo Llinas Rodolfo is a given name. Notable people with the name include: * Rodolfo (footballer, born 1992), Brazilian footballer Rodolfo José da Silva Bardella * Rodolfo Albano III, Filipino politician * Rodolfo Vera Quizon Sr. (1928-2012), Filipino actor ...
(Llinas and Hess (1977) and Llinas and Sugimori (1980)). P-type calcium channels were named after Purkinje cells, where they were initially encountered (Llinas et al. 1989), which are crucial in cerebellar function. Activation of the Purkinje cell by climbing fibers can shift its activity from a quiet state to a spontaneously active state and vice versa, serving as a kind of toggle switch. These findings have been challenged by a study suggesting that such toggling by climbing-fiber inputs occurs predominantly in anaesthetized animals and that Purkinje cells in awake behaving animals, in general, operate almost continuously in the upstate. But this latter study has itself been challenged and Purkinje cell toggling has since been observed in awake cats. A computational model of the Purkinje cell has shown intracellular calcium computations to be responsible for toggling. Findings have suggested that Purkinje cell dendrites release
endocannabinoid Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tet ...
s that can transiently downregulate both excitatory and inhibitory synapses. The intrinsic activity mode of Purkinje cells is set and controlled by the sodium-potassium pump. This suggests that the pump might not be simply a
homeostatic In biology, homeostasis (British also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism an ...
, "housekeeping" molecule for ionic gradients. Instead, it could be a
computation Computation is any type of arithmetic or non-arithmetic calculation that follows a well-defined model (e.g., an algorithm). Mechanical or electronic devices (or, historically, people) that perform computations are known as ''computers''. An esp ...
element in the cerebellum and the brain. Indeed, a
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
in the - pump causes rapid onset dystonia parkinsonism; its symptoms indicate that it is a pathology of cerebellar computation. Furthermore, using the poison
ouabain Ouabain or (from Somali ''waabaayo'', "arrow poison" through French ''ouabaïo'') also known as g-strophanthin, is a plant derived toxic substance that was traditionally used as an arrow poison in eastern Africa for both hunting and warfare. Ou ...
to block - pumps in the cerebellum of a live mouse induces
ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...
and
dystonia Dystonia is a neurological hyperkinetic movement disorder in which sustained or repetitive muscle contractions result in twisting and repetitive movements or abnormal fixed postures. The movements may resemble a tremor. Dystonia is often int ...
. Numerical modeling of experimental data suggests that, in vivo, the - pump produces long quiescent punctuations (>> 1 s) to Purkinje neuron firing; these may have a computational role.
Alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...
inhibits - pumps in the cerebellum and this is likely how it corrupts cerebellar computation and body co-ordination.


Clinical significance

In humans, Purkinje cells can be harmed by a variety causes: toxic exposure, e.g. to alcohol or lithium;
autoimmune disease An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...
s; genetic mutations causing spinocerebellar ataxias,
gluten ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...
, Unverricht-Lundborg disease, or
autism The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...
; and neurodegenerative diseases that are not known to have a genetic basis, such as the cerebellar type of multiple system atrophy or sporadic ataxias. Gluten ataxia is an autoimmune disease triggered by the ingestion of
gluten Gluten is a structural protein naturally found in certain cereal grains. Although "gluten" often only refers to wheat proteins, in medical literature it refers to the combination of prolamin and glutelin proteins naturally occurring in all grai ...
. The death of Purkinje cells as a result of gluten exposure is irreversible. Early diagnosis and treatment with a
gluten-free diet A gluten-free diet (GFD) is a nutritional plan that strictly excludes gluten, which is a mixture of proteins found in wheat (and all of its species and hybrids, such as spelt, kamut, and triticale), as well as barley, rye, and oats. The incl ...
can improve ataxia and prevent its progression. Less than 10% of people with gluten ataxia present any gastrointestinal symptom, yet about 40% have intestinal damage. It accounts for 40% of ataxias of unknown origin and 15% of all ataxias. The
neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophi ...
spinocerebellar ataxia type 1 Spinocerebellar ataxia type 1 (SCA1) is a rare autosomal dominant disorder, which, like other spinocerebellar ataxias, is characterized by neurological symptoms including dysarthria, hypermetric saccades, and ataxia of gait and stance. This cere ...
(SCA1) is caused by an unstable polyglutamine expansion within the Ataxin 1 protein. This defect in Ataxin 1 protein causes impairment of
mitochondria A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...
in Purkinje cells, leading to premature degeneration of the Purkinje cells. As a consequence,
motor coordination Motor coordination is the orchestrated movement of multiple body parts as required to accomplish intended actions, like walking. This coordination is achieved by adjusting kinematic and kinetic parameters associated with each body part involved in ...
declines and eventually death ensues. Some domestic animals can develop a condition where the Purkinje cells begin to atrophy shortly after birth, called cerebellar abiotrophy. It can lead to symptoms such as
ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...
, intention tremors, hyperreactivity, lack of
menace reflex The menace response is one of three forms of blink reflex. It is the reflex blinking that occurs in response to the rapid approach of an object. The reflex comprises blinking of the eyelids, in order to protect the eyes from potential damage, but m ...
, stiff or high-stepping gait, apparent lack of awareness of foot position (sometimes standing or walking with a foot knuckled over), and a general inability to determine space and distance. A similar condition known as
cerebellar hypoplasia Cerebellar hypoplasia is characterized by reduced cerebellar volume, even though cerebellar shape is (near) normal. It consists of a heterogeneous group of disorders of cerebellar maldevelopment presenting as early-onset non–progressive conge ...
occurs when Purkinje cells fail to develop'' in utero'' or die off before birth. The genetic conditions
ataxia telangiectasia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...
and Niemann Pick disease type C, as well as cerebellar
essential tremor Essential tremor (ET), also called benign tremor, familial tremor, and idiopathic tremor, is a medical condition characterized by involuntary rhythmic contractions and relaxations ( oscillations or twitching movements) of certain muscle groups in ...
, involve the progressive loss of Purkinje cells. In Alzheimer's disease, spinal pathology is sometimes seen, as well as loss of dendritic branches of the Purkinje cells. Purkinje cells can also be damaged by the
rabies Rabies is a viral disease that causes encephalitis in humans and other mammals. Early symptoms can include fever and tingling at the site of exposure. These symptoms are followed by one or more of the following symptoms: nausea, vomiting, ...
virus as it migrates from the site of infection in the periphery to the central nervous system. Note: not peer-reviewed.


Etymology

Purkinje cells are named after the Czech scientist Jan Evangelista Purkyně, who discovered them in 1839.


References


External links


Cell Image Library - PurkinjeDisorders of cerebellumNIF Search - Purkinje Cell
via the
Neuroscience Information Framework The Neuroscience Information Framework is a repository of global neuroscience web resources, including experimental, clinical, and translational neuroscience databases, knowledge bases, atlases, and genetic/genomic resources and provides many auth ...


Further reading

* * * * {{DEFAULTSORT:Purkinje Cell Neurons Cerebellum Central nervous system neurons