-
Journal of Integrative Neuroscience Jan 2022Apoptosis, autophagy and necrosis are the three main types of programmed cell death. One or more of these types of programmed cell death may take place in neurons... (Review)
Review
Apoptosis, autophagy and necrosis are the three main types of programmed cell death. One or more of these types of programmed cell death may take place in neurons leading to their death in various neurodegenerative disorders in humans. Purkinje neurons (PNs) are among the most highly vulnerable population of neurons to cell death in response to intrinsic hereditary diseases or extrinsic toxic, hypoxic, ischemic, and traumatic injury. In this review, we will describe the three main types of programmed cell death, including the molecular mechanisms and the sequence of events in each of them, and thus illustrating the intracellular proteins that mediate and regulate each of these types. Then, we will discuss the role of Ca2+ in PN function and increased vulnerability to cell death. Additionally, PN death will be described in animal models, namely lurcher mutant mouse and shaker mutant rat, in order to illustrate the potential therapeutic implications of programmed cell death in PNs by reviewing the previous studies that were carried out to interfere with the programmed cell death in an attempt to rescue PNs from death.
Topics: Animals; Apoptosis; Autophagy; Cerebellum; Humans; Mice; Necrosis; Neurodegenerative Diseases; Purkinje Cells; Rats
PubMed: 35164466
DOI: 10.31083/j.jin2101030 -
Neuroscience Research Nov 2019Long-term depression at parallel fiber-Purkinje cell synapses plays a principal role in learning in the cerebellum, which acts as a supervised learning machine. Recent... (Review)
Review
Long-term depression at parallel fiber-Purkinje cell synapses plays a principal role in learning in the cerebellum, which acts as a supervised learning machine. Recent experiments demonstrate various forms of synaptic plasticity at different sites within the cerebellum. In this article, we take into consideration synaptic plasticity at parallel fiber-molecular layer interneuron synapses as well as at parallel fiber-Purkinje cell synapses, and propose that the cerebellar cortex performs reinforcement learning, another form of learning that is more capable than supervised learning. We posit that through the use of reinforcement learning, the need for explicit teacher signals for learning in the cerebellum is eliminated; instead, learning can occur via responses from evaluative feedback. We demonstrate the learning capacity of cerebellar reinforcement learning using simple computer simulations of delay eyeblink conditioning and the cart-pole balancing task.
Topics: Animals; Blinking; Cerebellar Cortex; Computer Simulation; Humans; Interneurons; Learning; Neuronal Plasticity; Purkinje Cells; Synapses
PubMed: 30922970
DOI: 10.1016/j.neures.2019.03.001 -
Seminars in Cell & Developmental Biology Dec 2022The HERC protein family is one of three subfamilies of Homologous to E6AP C-terminus (HECT) E3 ubiquitin ligases. Six HERC genes have been described in humans, two of... (Review)
Review
The HERC protein family is one of three subfamilies of Homologous to E6AP C-terminus (HECT) E3 ubiquitin ligases. Six HERC genes have been described in humans, two of which encode Large HERC proteins -HERC1 and HERC2- with molecular weights above 520 kDa that are constitutively expressed in the brain. There is a large body of evidence that mutations in these Large HERC genes produce clinical syndromes in which key neurodevelopmental events are altered, resulting in intellectual disability and other neurological disorders like epileptic seizures, dementia and/or signs of autism. In line with these consequences in humans, two mice carrying mutations in the Large HERC genes have been studied quite intensely: the tambaleante mutant for Herc1 and the Herc2 mutant for Herc2. In both these mutant mice there are clear signs that autophagy is dysregulated, eliciting cerebellar Purkinje cell death and impairing motor control. The tambaleante mouse was the first of these mice to appear and is the best studied, in which the Herc1 mutation elicits: (i) delayed neural transmission in the peripheral nervous system; (ii) impaired learning, memory and motor control; and (iii) altered presynaptic membrane dynamics. In this review, we discuss the information currently available on HERC proteins in the nervous system and their biological activity, the dysregulation of which could explain certain neurodevelopmental syndromes and/or neurodegenerative diseases.
Topics: Animals; Humans; Mice; Mutation; Purkinje Cells; Synaptic Transmission; Ubiquitin-Protein Ligases; Neurodevelopmental Disorders; Neurodegenerative Diseases
PubMed: 34848147
DOI: 10.1016/j.semcdb.2021.11.017 -
Molecular and Cellular Neurosciences Jul 2022A hexanucleotide (GGGGCC) repeat expansion in the first intron of the C9ORF72 gene is the most frequently reported genetic cause of amyotrophic lateral sclerosis (ALS)...
A hexanucleotide (GGGGCC) repeat expansion in the first intron of the C9ORF72 gene is the most frequently reported genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The cerebellum has not traditionally been thought to be involved in the pathogenesis of C9ORF72-associated ALS/FTD, but recent evidence suggested a potential role. C9ORF72 is highly expressed in the cerebellum. Decreased C9ORF72 transcript and protein levels were detected in the postmortem cerebellum, suggesting a loss-of-function effect of C9ORF72 mutation. This study investigated the role of loss of C9ORF72 function using a C9orf72 knockout mouse line. C9orf72 deficiency led to motor impairment in rotarod, beam-walking, paw-print, open-field, and grip-strength tests. Purkinje cells are the sole output neurons in the cerebellum, and we next determined their involvement in the motor phenotypes. We found hyperactivity of Purkinje cells in the C9orf72 knockout mouse accompanied by a significant increase of the large-conductance calcium-activated potassium channel (BK) protein in the cerebellum. The link between BK and Purkinje cell firing was demonstrated by the acute application of the BK activator that increased the firing frequency of the Purkinje cells ex vivo. In vivo chemogenetic activation of Purkinje cells in wild-type mice led to similar motor deficits in rotarod and beam-walking tests. Our results highlight that C9ORF72 loss alters the activity of the Purkinje cell and potentially the pathogenesis of the disease. Manipulating the Purkinje cell firing or cerebellar output may contribute to C9ORF72-associated ALS/FTD treatment.
Topics: Animals; Mice; Amyotrophic Lateral Sclerosis; C9orf72 Protein; DNA Repeat Expansion; Frontotemporal Dementia; Mice, Knockout; Purkinje Cells; Disease Models, Animal
PubMed: 35843530
DOI: 10.1016/j.mcn.2022.103756 -
Nature Communications Sep 2023Social recognition memory (SRM) is a key determinant of social interactions. While the cerebellum emerges as an important region for social behavior, how cerebellar...
Social recognition memory (SRM) is a key determinant of social interactions. While the cerebellum emerges as an important region for social behavior, how cerebellar activity affects social functions remains unclear. We selectively increased the excitability of molecular layer interneurons (MLIs) to suppress Purkinje cell firing in the mouse cerebellar vermis. Chemogenetic perturbation of MLIs impaired SRM without affecting sociability, anxiety levels, motor coordination or object recognition. Optogenetic interference of MLIs during distinct phases of a social recognition test revealed the cerebellar engagement in the retrieval, but not encoding, of social information. c-Fos mapping after the social recognition test showed that cerebellar manipulation decreased brain-wide interregional correlations and altered network structure from medial prefrontal cortex and hippocampus-centered to amygdala-centered modules. Anatomical tracing demonstrated hierarchical projections from the central cerebellum to the social brain network integrating amygdalar connections. Our findings suggest that the cerebellum organizes the neural matrix necessary for SRM.
Topics: Mice; Animals; Cerebellar Vermis; Cerebellum; Purkinje Cells; Interneurons; Memory Disorders
PubMed: 37752149
DOI: 10.1038/s41467-023-41744-2 -
Signal Transduction and Targeted Therapy Jun 2022Cerebellar ataxias are characterized by a progressive decline in motor coordination, but the specific output circuits and underlying pathological mechanism remain poorly...
Cerebellar ataxias are characterized by a progressive decline in motor coordination, but the specific output circuits and underlying pathological mechanism remain poorly understood. Through cell-type-specific manipulations, we discovered a novel GABAergic Purkinje cell (PC) circuit in the cerebellar IV/V lobe that projected to CaMKIIα neurons in the fastigial nucleus (FN), which regulated sensorimotor coordination. Furthermore, transcriptomics profiling analysis revealed various cerebellar neuronal identities, and we validated that biorientation defective 1 (BOD1) played an important role in the circuit of IV/V lobe to FN. BOD1 deficit in PCs of IV/V lobe attenuated the excitability and spine density of PCs, accompany with ataxia behaviors. Instead, BOD1 enrichment in PCs of IV/V lobe reversed the hyperexcitability of CaMKIIα neurons in the FN and ameliorated ataxia behaviors in L7-Cre; BOD1 mice. Together, these findings further suggest that specific regulation of the cerebellar IV/V lobe→ FN circuit might provide neuromodulatory targets for the treatment of ataxia behaviors.
Topics: Animals; Ataxia; Cerebellar Nuclei; Mice; Neurons; Purkinje Cells
PubMed: 35641478
DOI: 10.1038/s41392-022-00989-x -
Nature Communications Aug 2023Synaptic adhesion molecules (SAMs) shape the structural and functional properties of synapses and thereby control the information processing power of neural circuits....
Synaptic adhesion molecules (SAMs) shape the structural and functional properties of synapses and thereby control the information processing power of neural circuits. SAMs are broadly expressed in the brain, suggesting that they may instruct synapse formation and specification via a combinatorial logic. Here, we generate sextuple conditional knockout mice targeting all members of the two major families of presynaptic SAMs, Neurexins and leukocyte common antigen-related-type receptor phospho-tyrosine phosphatases (LAR-PTPRs), which together account for the majority of known trans-synaptic complexes. Using synapses formed by cerebellar Purkinje cells onto deep cerebellar nuclei as a model system, we confirm that Neurexins and LAR-PTPRs themselves are not essential for synapse assembly. The combinatorial deletion of both neurexins and LAR-PTPRs, however, decreases Purkinje-cell synapses on deep cerebellar nuclei, the major output pathway of cerebellar circuits. Consistent with this finding, combined but not separate deletions of neurexins and LAR-PTPRs impair motor behaviors. Thus, Neurexins and LAR-PTPRs are together required for the assembly of a functional cerebellar circuit.
Topics: Animals; Mice; Cerebellum; Purkinje Cells; Brain; Cognition; Mice, Knockout; Phosphotyrosine; Protein Tyrosine Phosphatases; Receptor-Like Protein Tyrosine Phosphatases, Class 2
PubMed: 37591863
DOI: 10.1038/s41467-023-40526-0 -
Neuroscience May 2021As a tribute to Masao Ito, we propose a model of cerebellar learning that incorporates and extends his original model. We suggest four principles that align well with... (Review)
Review
As a tribute to Masao Ito, we propose a model of cerebellar learning that incorporates and extends his original model. We suggest four principles that align well with conclusions from multiple cerebellar learning systems. (1) Climbing fiber inputs to the cerebellum drive early, fast, poorly-retained learning in the parallel fiber to Purkinje cell synapse. (2) Learned Purkinje cell outputs drive late, slow, well-retained learning in non-Purkinje cell inputs to neurons in the cerebellar nucleus, transferring learning from the cortex to the nucleus. (3) Recurrent feedback from Purkinje cells to the inferior olive, through interneurons in the cerebellar nucleus, limits the magnitude of fast, early learning in the cerebellar cortex. (4) Functionally different inputs are subjected to plasticity in the cerebellar cortex versus the cerebellar nucleus. A computational neural circuit model that is based on these principles mimics a large amount of neural and behavioral data obtained from the smooth pursuit eye movements of monkeys.
Topics: Animals; Cerebellar Nuclei; Cerebellum; Olivary Nucleus; Purkinje Cells; Pursuit, Smooth
PubMed: 32866603
DOI: 10.1016/j.neuroscience.2020.08.026 -
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 -
Life Science Alliance Sep 2023Niemann-Pick disease type C1 (NPC1) is a fatal lysosomal storage disorder characterized by progressive neuronal degeneration. Its key pathogenic events remain largely...
Niemann-Pick disease type C1 (NPC1) is a fatal lysosomal storage disorder characterized by progressive neuronal degeneration. Its key pathogenic events remain largely unknown. We have, herein, found that neonatal BM-derived cell transplantation can ameliorate Purkinje cell degeneration in NPC1 mice. We subsequently addressed the impact of the peripheral immune system on the neuropathogenesis observed in NPC1 mice. The depletion of mature lymphocytes promoted NPC1 phenotypes, thereby suggesting a neuroprotective effect of lymphocytes. Moreover, the peripheral infusion of CD4-positive cells (specifically, of regulatory T cells) from normal healthy donor ameliorated the cerebellar ataxic phenotype and enhanced the survival of Purkinje cells. Conversely, the depletion of regulatory T cells enhanced the onset of the neurological phenotype. On the other hand, circulating inflammatory monocytes were found to be involved in the progression of Purkinje cell degeneration, whereas the depletion of resident microglia had little effect. Our findings reveal a novel role of the adaptive and the innate immune systems in NPC1 neuropathology.
Topics: Mice; Animals; Purkinje Cells; Niemann-Pick Disease, Type C; Cerebellum; Immune System; Microglia
PubMed: 37369603
DOI: 10.26508/lsa.202201881