Purkinje cells orPurkinje neurons, named for Czech physiologistJan Evangelista Purkyně who identified them in 1837,[2] are a unique type of prominent, largeneuron located in thecerebellarcortex of thebrain. With their flask-shaped cell bodies, many branchingdendrites, and a single longaxon, these cells are essential for controlling motor activity. Purkinje cells mainly release GABA (gamma-aminobutyric acid) 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.[3][4]
Neurons (Purkinje cells) located in the cerebellumTransverse section of a cerebellarfolium (Purkinje cell labeled at center top)Silver stain of cerebellum showing Purkinje cellsPurkinje cells.Bielschowsky stain.Confocal microscope image of cerebellar Purkinje cells expressingtdTomato
Each adult Purkinje cell receives approximately 500 climbing fiber synapses, all originating from a single climbing fiber from the inferior olive.[7] This has led to the notion that a "highly conserved one-to-one relationship renders Purkinje dendrites into a single computational compartment".[8] However, multi-innervation has now been found that "occurs" in mice among the subset of Purkinje cells with multiple primary dendrites, a dendritic motif that is uncommon in rodents but "predominant" in humans.[8]
Both basket and stellate cells (found in the cerebellarmolecular layer) provideinhibitory (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 allmotor coordination in the cerebellar cortex.
ThePurkinje layer of the cerebellum, which contains the cell bodies of the Purkinje cells andBergmann glia, express a large number of unique genes.[9] Purkinje-specific gene markers were also proposed by comparing the transcriptome of Purkinje-deficient mice with that of wild-type mice.[10] One illustrative example is the Purkinje cell protein 4 (PCP4) inknockout mice, which exhibit impaired locomotor learning and markedly alteredsynaptic plasticity in Purkinje neurons.[11][12] PCP4 accelerates both the association and dissociation ofcalcium (Ca2+) withcalmodulin (CaM) in the cytoplasm of Purkinje cells, and its absence impairs the physiology of these neurons.[11][12][13][14]
Mammalian embryonic research has detailed the neurogenic origins of Purkinje cells.[15] 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.[16] Purkinje cells are specifically generated from progenitors in the ventricular neuroepithelium of the embryonic cerebellar primordium.[17] 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.[18] 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 thatbone marrow 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.[19][20][21][22][23] Further evidence points yet towards the possibility of a commonstem cell ancestor among Purkinje neurons,B-lymphocytes andaldosterone-producingcells of the humanadrenal cortex.[22]
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.[24]
Purkinje cells show spontaneous electrophysiological activity in the form of trains of spikes both sodium-dependent and calcium-dependent. This was initially shown byRodolfo Llinas (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.[25] 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.[26] But this latter study has itself been challenged[27] and Purkinje cell toggling has since been observed in awake cats.[28] A computational model of the Purkinje cell has shown intracellular calcium computations to be responsible for toggling.[29]
Findings have suggested that Purkinje cell dendrites releaseendocannabinoids that can transiently downregulate both excitatory and inhibitory synapses.[30] The intrinsic activity mode of Purkinje cells is set and controlled by thesodium-potassium pump.[31] This suggests that the pump might not be simply ahomeostatic, "housekeeping" molecule for ionic gradients. Instead, it could be acomputation element in the cerebellum and the brain.[32] Indeed, amutation in theNa+ -K+ pump causes rapid onset dystonia parkinsonism; its symptoms indicate that it is a pathology of cerebellar computation.[33] Furthermore, using the poisonouabain to blockNa+ -K+ pumps in the cerebellum of a live mouse inducesataxia anddystonia.[34] Numerical modeling of experimental data suggests that, in vivo, theNa+ -K+ pump produces long quiescent punctuations (>> 1 s) to Purkinje neuron firing; these may have a computational role.[35]Alcohol inhibitsNa+ -K+ pumps in the cerebellum and this is likely how it corrupts cerebellar computation and body co-ordination.[36][37]
In humans, Purkinje cells can be harmed by a variety of causes: toxic exposure, e.g. to alcohol or lithium;autoimmune diseases; genetic mutations causing spinocerebellar ataxias,gluten ataxia,Unverricht-Lundborg disease, orautism; and neurodegenerative diseases that are not known to have a genetic basis, such as the cerebellar type of multiple system atrophy or sporadic ataxias.[38][39]
Gluten ataxia is an autoimmune disease triggered by the ingestion ofgluten.[40] The death of Purkinje cells as a result of gluten exposure is irreversible. Early diagnosis and treatment with agluten-free diet can improve ataxia and prevent its progression.[38][41] Less than 10% of people with gluten ataxia present any gastrointestinal symptom, yet about 40% have intestinal damage.[41] It accounts for 40% of ataxias of unknown origin and 15% of all ataxias.[41]
Some domestic animals can develop a condition where the Purkinje cells begin to atrophy shortly after birth, calledcerebellar abiotrophy. It can lead to symptoms such asataxia, intention tremors, hyperreactivity, lack ofmenace reflex, 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.[43] A similar condition known ascerebellar hypoplasia occurs when Purkinje cells fail to develop in utero or die off before birth.
The genetic conditionsataxia telangiectasia andNiemann Pick disease type C, as well as cerebellaressential tremor, 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.[44] Purkinje cells can also be damaged by therabies virus as it migrates from the site of infection in the periphery to the central nervous system.[45]
^Purkinje, J. E. (1837). Neueste Untersuchungen aus der Nerven und Hirn Anatomie. Bericht über die Versammlung deutscher Naturforscher und Aerzte in Prag im September, 1883, 177-180.
^Purves D, Augustine GJ, Fitzpatrick D, Hall WC, LaMantia A, McNamara JO, and White LE (2008).Neuroscience. 4th ed. Sinauer Associates. pp. 432–4.ISBN978-0-87893-697-7.
^Tyrrell, T; Willshaw, D (1992-05-29). "Cerebellar cortex: its simulation and the relevance of Marr's theory".Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences.336 (1277):239–57.Bibcode:1992RSPTB.336..239T.doi:10.1098/rstb.1992.0059.PMID1353267.
^Rong, Y; Wang T; Morgan J (2004). "Identification of candidate purkinje cell-specific markers by gene expression profiling in wild-type and pcd3j mice".Molecular Brain Research.13 (2):128–145.doi:10.1016/j.molbrainres.2004.10.015.PMID15582153.
^Jaber M (2017). "The cerebellum as a major player in motor disturbances related to Autistic Syndrome Disorders".Encephale (Review).43 (2):170–175.doi:10.1016/j.encep.2016.03.018.PMID27616580.
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