-
Nature Communications Jul 2023The classification of neuronal subpopulations has significantly advanced, yet its relevance for behavior remains unclear. The highly organized flocculus of the...
The classification of neuronal subpopulations has significantly advanced, yet its relevance for behavior remains unclear. The highly organized flocculus of the cerebellum, known to fine-tune multi-axial eye movements, is an ideal substrate for the study of potential functions of neuronal subpopulations. Here, we demonstrate that its recently identified subpopulations of 9+ and 9- Purkinje cells exhibit an intermediate Aldolase C expression and electrophysiological profile, providing evidence for a graded continuum of intrinsic properties among PC subpopulations. By identifying and utilizing two Cre-lines that genetically target these floccular domains, we show with high spatial specificity that these subpopulations of Purkinje cells participate in separate micromodules with topographically organized connections. Finally, optogenetic excitation of the respective subpopulations results in movements around the same axis in space, yet with distinct kinematic profiles. These results indicate that Purkinje cell subpopulations integrate in discrete circuits and mediate particular parameters of single movements.
Topics: Purkinje Cells; Biomechanical Phenomena; Eye Movements; Cerebellum; Movement
PubMed: 37468512
DOI: 10.1038/s41467-023-40111-5 -
Cerebellum (London, England) Apr 2016Synaptic plasticity at the parallel fiber to Purkinje cell synapse has long been considered a cellular correlate for cerebellar motor learning. Functionally, long-term... (Review)
Review
Synaptic plasticity at the parallel fiber to Purkinje cell synapse has long been considered a cellular correlate for cerebellar motor learning. Functionally, long-term depression and long-term potentiation at these synapses seem to be the reverse of each other, with both pre- and post-synaptic expression occurring in both. However, different cerebellar motor learning paradigms have been shown to be asymmetric and not equally reversible. Here, we discuss the asymmetric reversibility shown in the vestibulo-ocular reflex and eyeblink conditioning and suggest that different cellular plasticity mechanisms might be recruited under different conditions leading to unequal reversibility.
Topics: Animals; Cerebellum; Humans; Learning; Long-Term Potentiation; Neuronal Plasticity; Purkinje Cells; Synapses
PubMed: 25578035
DOI: 10.1007/s12311-014-0635-7 -
Journal of Molecular and Cellular... Nov 2008Cardiac Purkinje fibers, due to their unique anatomical location, cell structure and electrophysiologic characteristics, play an important role in cardiac conduction and... (Review)
Review
Cardiac Purkinje fibers, due to their unique anatomical location, cell structure and electrophysiologic characteristics, play an important role in cardiac conduction and arrhythmogenesis. Purkinje cell action potentials are longer than their ventricular counterpart, and display two levels of resting potential. Purkinje cells provide for rapid propagation of the cardiac impulse to ventricular cells and have pacemaker and triggered activity, which differs from ventricular cells. Additionally, a unique intracellular Ca2+ release coordination has been revealed recently for the normal Purkinje cell. However, since the isolation of single Purkinje cells is difficult, particularly in small animals, research using Purkinje cells has been restricted. This review concentrates on comparison of Purkinje and ventricular cells in the morphology of the action potential, ionic channel function and molecular determinants by summarizing our present day knowledge of Purkinje cells.
Topics: Action Potentials; Animals; Calcium; Connexins; Female; Heart Ventricles; Humans; Ion Channels; Ions; Male; Models, Biological; Potassium; Protein Isoforms; Purkinje Cells; Sodium
PubMed: 18778712
DOI: 10.1016/j.yjmcc.2008.08.001 -
Cerebellum (London, England) Aug 2016Several lines of evidence show that classical or Pavlovian conditioning of blink responses depends on the cerebellum. Recordings from cerebellar Purkinje cells that... (Review)
Review
Several lines of evidence show that classical or Pavlovian conditioning of blink responses depends on the cerebellum. Recordings from cerebellar Purkinje cells that control the eyelid and the conditioned blink show that during training with a conditioning protocol, a Purkinje cell develops a pause response to the conditional stimulus. This conditioned cellular response has many of the properties that characterise the overt blink. The present paper argues that the learned Purkinje cell pause response is the memory trace and main driver of the overt conditioned blink and that it explains many well-known behavioural phenomena.
Topics: Animals; Blinking; Conditioning, Classical; Conditioning, Eyelid; Memory; Purkinje Cells
PubMed: 26400585
DOI: 10.1007/s12311-015-0722-4 -
Neuroscience May 2021Cerebellar development has a remarkably protracted morphogenetic timeline that is coordinated by multiple cell types. Here, we discuss the intriguing cellular... (Review)
Review
Cerebellar development has a remarkably protracted morphogenetic timeline that is coordinated by multiple cell types. Here, we discuss the intriguing cellular consequences of interactions between inhibitory Purkinje cells and excitatory granule cells during embryonic and postnatal development. Purkinje cells are central to all cerebellar circuits, they are the first cerebellar cortical neurons to be born, and based on their cellular and molecular signaling, they are considered the master regulators of cerebellar development. Although rudimentary Purkinje cell circuits are already present at birth, their connectivity is morphologically and functionally distinct from their mature counterparts. The establishment of the Purkinje cell circuit with its mature firing properties has a temporal dependence on cues provided by granule cells. Granule cells are the latest born, yet most populous, neuronal type in the cerebellar cortex. They provide a combination of mechanical, molecular and activity-based cues that shape the maturation of Purkinje cell structure, connectivity and function. We propose that the wiring of Purkinje cells for function falls into two developmental phases: an initial phase that is guided by intrinsic mechanisms and a later phase that is guided by dynamically-acting cues, some of which are provided by granule cells. In this review, we highlight the mechanisms that granule cells use to help establish the unique properties of Purkinje cell firing.
Topics: Cerebellum; Humans; Infant, Newborn; Interneurons; Neurogenesis; Neurons; Purkinje Cells
PubMed: 32554107
DOI: 10.1016/j.neuroscience.2020.06.010 -
Experimental Neurology Nov 2023Purkinje 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...
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 -
ELife Apr 2020Although the cerebellum is traditionally associated with balance and motor function, it also plays wider roles in affective and cognitive behaviors. Evidence suggests...
Although the cerebellum is traditionally associated with balance and motor function, it also plays wider roles in affective and cognitive behaviors. Evidence suggests that the cerebellar vermis may regulate aggressive behavior, though the cerebellar circuits and patterns of activity that influence aggression remain unclear. We used optogenetic methods to bidirectionally modulate the activity of spatially-delineated cerebellar Purkinje cells to evaluate the impact on aggression in mice. Increasing Purkinje cell activity in the vermis significantly reduced the frequency of attacks in a resident-intruder assay. Reduced aggression was not a consequence of impaired motor function, because optogenetic stimulation did not alter motor performance. In complementary experiments, optogenetic inhibition of Purkinje cells in the vermis increased the frequency of attacks. These results suggest Purkinje cell activity in the cerebellar vermis regulates aggression, and further support the importance of the cerebellum in driving affective behaviors that could contribute to neurological disorders.
Topics: Aggression; Animals; Behavior, Animal; Cerebellar Vermis; Cerebellum; Mice; Optogenetics; Purkinje Cells
PubMed: 32343225
DOI: 10.7554/eLife.53229 -
Brain Pathology (Zurich, Switzerland) Nov 2015Cerebellar ataxia commonly occurs in multiple sclerosis, particularly in chronic progressive disease. Previous reports have highlighted both white matter and grey matter...
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 -
Proceedings of the National Academy of... Jun 2020Comparative transcriptomics between differentiating human pluripotent stem cells (hPSCs) and developing mouse neurons offers a powerful approach to compare genetic and... (Comparative Study)
Comparative Study
Comparative transcriptomics between differentiating human pluripotent stem cells (hPSCs) and developing mouse neurons offers a powerful approach to compare genetic and epigenetic pathways in human and mouse neurons. To analyze human Purkinje cell (PC) differentiation, we optimized a protocol to generate human pluripotent stem cell-derived Purkinje cells (hPSC-PCs) that formed synapses when cultured with mouse cerebellar glia and granule cells and fired large calcium currents, measured with the genetically encoded calcium indicator jRGECO1a. To directly compare global gene expression of hPSC-PCs with developing mouse PCs, we used translating ribosomal affinity purification (TRAP). As a first step, we used TRAP mice to profile actively transcribed genes in developing postnatal mouse PCs and used metagene projection to identify the most salient patterns of PC gene expression over time. We then created a transgenic - TRAP hPSC line to profile gene expression in differentiating hPSC-PCs, finding that the key gene expression pathways of differentiated hPSC-PCs most closely matched those of late juvenile mouse PCs (P21). Comparative bioinformatics identified classical PC gene signatures as well as novel mitochondrial and autophagy gene pathways during the differentiation of both mouse and human PCs. In addition, we identified genes expressed in hPSC-PCs but not mouse PCs and confirmed protein expression of a novel human PC gene, CD40LG, expressed in both hPSC-PCs and native human cerebellar tissue. This study therefore provides a direct comparison of hPSC-PC and mouse PC gene expression and a robust method for generating differentiated hPSC-PCs with human-specific gene expression for modeling developmental and degenerative cerebellar disorders.
Topics: Animals; Cell Differentiation; Humans; Mice; Pluripotent Stem Cells; Proteins; Purkinje Cells; Transcriptome
PubMed: 32546527
DOI: 10.1073/pnas.2000102117 -
Acta Neuropathologica Communications May 2016Purkinje 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...
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