Review

Authors: Court Hull, Wade G Regehr

The cerebellar cortex is an important system for relating neural circuits and learning. Its promise reflects the longstanding idea that it contains simple, repeated circuit modules with only a few cell types and a single plasticity mechanism that mediates learning according to classical Marr-Albus models. However, emerging data have revealed surprising diversity in neuron types, synaptic connections, and plasticity mechanisms, both locally and regionally within the cerebellar cortex. In light of these findings, it is not surprising that attempts to generate a holistic model of cerebellar learning across different behaviors have not been successful. While the cerebellum remains an ideal system for linking neuronal function with behavior, it is necessary to update the cerebellar circuit framework to achieve its great promise. In this review, we highlight recent advances in our understanding of cerebellar-cortical cell types, synaptic connections, signaling mechanisms, and forms of plasticity that enrich cerebellar processing.

Topics: Cerebellar Cortex; Cerebellum; Learning; Neuronal Plasticity; Purkinje Cells

PubMed: 35803588
DOI: 10.1146/annurev-neuro-091421-125115

Review

Authors: Jaclyn Beckinghausen, Roy V Sillitoe

The cerebellum has a well-established role in controlling motor functions such coordination, balance, posture, and skilled learning. There is mounting evidence that it might also play a critical role in non-motor functions such as cognition and emotion. It is therefore not surprising that cerebellar defects are associated with a wide array of diseases including ataxia, dystonia, tremor, schizophrenia, dyslexia, and autism spectrum disorder. What is intriguing is that a seemingly uniform circuit that is often described as being "simple" should carry out all of these behaviors. Analyses of how cerebellar circuits develop have revealed that such descriptions massively underestimate the complexity of the cerebellum. The cerebellum is in fact highly patterned and organized around a series of parasagittal stripes and transverse zones. This topographic architecture partitions all cerebellar circuits into functional modules that are thought to enhance processing power during cerebellar dependent behaviors. What are arguably the most remarkable features of cerebellar topography are the developmental processes that produce them. This review is concerned with the genetic and cellular mechanisms that orchestrate cerebellar patterning. We place a major focus on how Purkinje cells control multiple aspects of cerebellar circuit assembly. Using this model, we discuss evidence for how "zebra-like" patterns in Purkinje cells sculpt the cerebellum, how specific genetic cues mediate the process, and how activity refines the patterns into an adult map that is capable of executing various functions. We also discuss how defective Purkinje cell patterning might impact the pathogenesis of neurological conditions.

Topics: Animals; Cerebellar Diseases; Cerebellum; Humans; Purkinje Cells

PubMed: 29746896
DOI: 10.1016/j.neulet.2018.05.013

Review

Authors: John H Freeman

The mechanisms underlying cerebellar learning are reviewed with an emphasis on old arguments and new perspectives on eyeblink conditioning. Eyeblink conditioning has been used for decades a model system for elucidating cerebellar learning mechanisms. The standard model of the mechanisms underlying eyeblink conditioning is that there two synaptic plasticity processes within the cerebellum that are necessary for acquisition of the conditioned response: (1) long-term depression (LTD) at parallel fiber-Purkinje cell synapses and (2) long-term potentiation (LTP) at mossy fiber-interpositus nucleus synapses. Additional Purkinje cell plasticity mechanisms may also contribute to eyeblink conditioning including LTP, excitability, and entrainment of deep nucleus activity. Recent analyses of the sensory input pathways necessary for eyeblink conditioning indicate that the cerebellum regulates its inputs to facilitate learning and maintain plasticity. Cerebellar learning during eyeblink conditioning is therefore a dynamic interactive process which maximizes responding to significant stimuli and suppresses responding to irrelevant or redundant stimuli. This article is part of a Special Issue entitled SI: Brain and Memory.

Topics: Animals; Cerebellum; Conditioning, Eyelid; Humans; Neuronal Plasticity; Purkinje Cells; Synapses

PubMed: 25289586
DOI: 10.1016/j.brainres.2014.09.062

Authors: Juliana Redondo, Kevin Kemp, Kelly Hares...

Cerebellar ataxia commonly occurs in multiple sclerosis, particularly in chronic progressive disease. Previous reports have highlighted both white matter and grey matter pathological changes within the cerebellum; and demyelination and inflammatory cell infiltrates appear commonly. As Purkinje cell axons are the sole output of the cerebellar cortex, understanding pathologic processes within these cells is crucial to develop strategies to prevent their loss and thus reduce ataxia. We studied pathologic changes occurring within Purkinje cells of the cerebellum. Using immunohistochemic techniques, we found changes in neurofilament phosphorylation states within Purkinje cells, including loss of dephosphorylated neurofilament and increased phosphorylated and hyperphosphorylated neurofilament. We also found Purkinje axonal spheroids and Purkinje cell loss, both of which occurred predominantly within areas of leucocortical demyelination within the cerebellar cortex. These changes have important implications for the study of cerebellar involvement in multiple sclerosis and may help design therapies to reduce the burden of ataxia in the condition.

Topics: Aged; Aged, 80 and over; Axons; Cell Death; Cerebellum; Cohort Studies; Female; Fluorescent Antibody Technique; Humans; Intermediate Filaments; Male; Middle Aged; Multiple Sclerosis; Phosphorylation; Purkinje Cells

PubMed: 25411024
DOI: 10.1111/bpa.12230

Authors: Kevin C Kemp, Amelia J Cook, Juliana Redondo...

Purkinje cell pathology is a common finding in a range of inherited and acquired cerebellar disorders, with the degree of Purkinje cell injury dependent on the underlying aetiology. Purkinje cells have an unparalleled resistance to insult and display unique regenerative capabilities within the central nervous system. Their response to cell injury is not typical of most neurons and likely represents both degenerative, compensatory and regenerative mechanisms. Here we present a pathological study showing novel and fundamental insights into Purkinje cell injury, remodelling and repair in Friedreich's ataxia; the most common inherited ataxia. Analysing post-mortem cerebellum tissue from patients who had Friedreich's ataxia, we provide evidence of significant injury to the Purkinje cell axonal compartment with relative preservation of both the perikaryon and its extensive dendritic arborisation. Axonal remodelling of Purkinje cells was clearly elevated in the disease. For the first time in a genetic condition, we have also shown a disease-related increase in the frequency of Purkinje cell fusion and heterokaryon formation in Friedreich's ataxia cases; with evidence that underlying levels of cerebellar inflammation influence heterokaryon formation. Our results together further demonstrate the Purkinje cell's unique plasticity and regenerative potential. Elucidating the biological mechanisms behind these phenomena could have significant clinical implications for manipulating neuronal repair in response to neurological injury.

Topics: Adult; Aged; Aged, 80 and over; Axons; Cohort Studies; Female; Friedreich Ataxia; Humans; Imaging, Three-Dimensional; Immunohistochemistry; Male; Microglia; Microscopy, Confocal; Middle Aged; Myelin Sheath; Neuroimmunomodulation; Neuronal Plasticity; Purkinje Cells

PubMed: 27215193
DOI: 10.1186/s40478-016-0326-3

Review

Authors: Martha L Streng, Laurentiu S Popa, Timothy J Ebner...

The climbing fiber-Purkinje cell circuit is one of the most powerful and highly conserved in the central nervous system. Climbing fibers exert a powerful excitatory action that results in a complex spike in Purkinje cells and normal functioning of the cerebellum depends on the integrity of climbing fiber-Purkinje cell synapse. Over the last 50 years, multiple hypotheses have been put forward on the role of the climbing fibers and complex spikes in cerebellar information processing and motor control. Central to these theories is the nature of the interaction between the low-frequency complex spike discharge and the high-frequency simple spike firing of Purkinje cells. This review examines the major hypotheses surrounding the action of the climbing fiber-Purkinje cell projection, discussing both supporting and conflicting findings. The review describes newer findings establishing that climbing fibers and complex spikes provide predictive signals about movement parameters and that climbing fiber input controls the encoding of behavioral information in the simple spike firing of Purkinje cells. Finally, we propose the dynamic encoding hypothesis for complex spike function that strives to integrate established and newer findings.

Topics: Action Potentials; Animals; Models, Neurological; Motor Activity; Olivary Nucleus; Purkinje Cells

PubMed: 29982917
DOI: 10.1007/s12311-018-0960-3

Authors: L T Lotta, K Conrad, D Cory-Slechta...

The p75 neurotrophin receptor (p75NTR) is normally expressed in cerebellar Purkinje cells throughout the lifespan. Children with autism spectrum behavior exhibit apparent cerebellar Purkinje cell loss. Cerebellar transcriptome changes seen in the murine prenatal valproate exposure model of autism include all of the proteins known to constitute the p75NTR interactome. p75NTR is a modulator of cytoplasmic and mitochondrial redox potential, and others have suggested that aberrant response to oxidant stress has a major role in the pathogenesis of autism. We have created Purkinje cell-selective p75NTR knockout mice that are the progeny of hemizygous Cre-Purkinje cell protein 2 C57Bl mice and p75NTR floxed C57Bl mice. These Cre-loxP mice exhibit complete knockout of p75NTR in ~50% of the cerebellar Purkinje cells. Relative to Cre-only mice and wild-type C57Bl mice, this results in a behavioral phenotype characterized by less allogrooming of (P<0.05; one-way analysis of variance) and socialization or fighting with (each P<0.05) other mice; less (1.2-fold) non-ambulatory exploration of their environment than wild-type (P<0.01) or Cre only (P<0.01) mice; and almost twofold more stereotyped jumping behavior than wild-type (P<0.05) or Cre (P<0.02) mice of the same strain. Wild-type mice have more complex dendritic arborization than Cre-loxP mice, with more neurites per unit area (P<0.025, Student's t-test), more perpendicular branches per unit area (P<0.025) and more short branches/long neurite (P<0.0005). Aberrant developmental regulation of expression of p75NTR in cerebellar Purkinje cells may contribute to the pathogenesis of autism.

Topics: Agonistic Behavior; Animals; Autistic Disorder; Disease Models, Animal; Gene Expression; Mice; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Purkinje Cells; Receptors, Nerve Growth Factor; Socialization; Stereotyped Behavior; Transcriptome

PubMed: 25072321
DOI: 10.1038/tp.2014.55

Authors: Mohammed Bahaaeldin, Carolin Bülte, Fabienne Luelsberg...

Autism spectrum disorders (ASD) have a complex pathogenesis thought to include both genetic and extrinsic factors. Among the latter, inflammation of the developing brain has recently gained growing attention. However, how genetic predisposition and inflammation might converge to precipitate autistic behavior remains elusive. Cerebellar structure and function are well known to be affected in autism. We therefore used cerebellar slice cultures to probe whether inflammatory stimulation and (over)expression of the autism susceptibility gene Engrailed-2 interact in shaping differentiation of Purkinje cells, key organizers of cerebellar histogenesis and function. We show that lipopolysaccharide treatment reduces Purkinje cell dendritogenesis and that this effect is enhanced by over-expression of Engrailed-2 in these cells. The effects of lipopolysaccharide can be blocked by inhibiting microglia proliferation and also by blocking tumor necrosis factor alpha receptor signaling, suggesting microglia and tumor necrosis factor alpha are major players in this scenario. These findings identify Purkinje cells as a potential integrator of genetic and environmental signals that lead to an autism-associated morphology.

Topics: Animals; Purkinje Cells; Mice; Homeodomain Proteins; Cell Differentiation; Nerve Tissue Proteins; Lipopolysaccharides; Inflammation; Cerebellum; Animals, Newborn; Microglia; Mice, Transgenic; Mice, Inbred C57BL

PubMed: 39609827
DOI: 10.1186/s12974-024-03301-6

Authors: Matthew Choe, Etty Cortés, Jean-Paul G Vonsattel...

INTRODUCTION

Purkinje cell loss has been documented in some, although not all, postmortem studies of essential tremor. Hence, there is considerable controversy concerning the presence of Purkinje cell loss in this disease. To date, few studies have been performed.

METHODS

Over the past 8 years, we have assembled 50 prospectively studied cases and 25 age-matched controls; none were reported in our previous large series of 33 essential tremor and 21 controls. In addition to methods used in previous studies, the current study used a random sampling approach to quantify Purkinje cells along the Purkinje cell layer with a mean of 217 sites examined in each specimen, allowing for extensive sampling of the Purkinje cell layer within the section. For the first time, we also quantified the distance between Purkinje cell bodies-a nearest neighbor analysis.

RESULTS

In the Purkinje cell count data collected from fifteen 100 × fields, cases had lower counts than controls in all three counting criteria (cell bodies, nuclei, and nucleoli; all P < 0.001). Purkinje cell linear density was also lower in cases than controls (all P < 0.001). Purkinje cell linear density obtained by random sampling was similarly lower in cases than controls in all three counting criteria (cell bodies, nuclei, and nucleoli, all P ≤ 0.005). In agreement with the quantitative Purkinje cell counts, the mean distance from one Purkinje cell body to another Purkinje cell body along the Purkinje cell layer was greater in cases than controls (P = 0.002).

CONCLUSIONS

These data provide support for the neurodegeneration of cerebellar Purkinje cells in essential tremor.

Topics: Aged; Aged, 80 and over; Autopsy; Cell Count; Cell Death; Cerebellum; Essential Tremor; Female; Humans; Male; Neurodegenerative Diseases; Purkinje Cells

PubMed: 26861543
DOI: 10.1002/mds.26490

Authors: Takamasa Kamei, Atsushi Tamada, Toshiya Kimura...

Purkinje cells are the sole output neurons of the cerebellar cortex and play central roles in the integration of cerebellum-related motor coordination and memory. The loss or dysfunction of Purkinje cells due to cerebellar atrophy leads to severe ataxia. Here we used in vivo transplantation to examine the function of human iPS cell-derived cerebellar progenitors in adult transgenic mice in which Purkinje-specific cell death occurs due to cytotoxicity of polyglutamines. Transplantation using cerebellar organoids (42-48 days in culture), which are rich in neural progenitors, showed a viability of >50% 4 weeks after transplantation. STEM121 grafted cells extended their processes toward the deep cerebellar nuclei, superior cerebellar peduncle, and vestibulocerebellar nuclei. The transplanted cells were mostly located in the white matter, and they were not found in the Purkinje cell layer. MAP2-positive fibers seen in the molecular layer of cerebellar cortex received VGluT2 inputs from climbing fibers. Transplanted neural progenitors overgrew in the host cerebellum but were suppressed by pretreatment with the γ-secretase inhibitor DAPT. Hyperproliferation was also suppressed by transplantation with more differentiated organoids (86 days in culture) or KIRREL2-positive cells purified by FACS sorting. Transplanted cells expressed Purkinje cell markers, GABA, CALB1 and L7, though they did not show fan-shaped morphology. We attempted to improve neuronal integration of stem cell-derived cerebellar progenitors by transplantation into the adult mouse, but this was not successfully achieved. Our findings in the present study contribute to regenerative medical application for cerebellar degeneration and provide new insights into cerebellar development in future.

Topics: Humans; Mice; Animals; Purkinje Cells; Induced Pluripotent Stem Cells; Cerebellum; Cerebellar Cortex; Mice, Transgenic

PubMed: 37634697
DOI: 10.1016/j.expneurol.2023.114511