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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 -
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 -
Alcohol (Fayetteville, N.Y.) Jun 2022Exposure to alcohol during pregnancy can kill developing fetal neurons and lead to fetal alcohol spectrum disorder (FASD) in the offspring. However, not all fetuses are...
INTRODUCTION
Exposure to alcohol during pregnancy can kill developing fetal neurons and lead to fetal alcohol spectrum disorder (FASD) in the offspring. However, not all fetuses are equally vulnerable to alcohol toxicity. These differences in vulnerability among individuals are likely due, at least in part, to genetic differences. Some genes encode neuroprotective molecules that act through signaling pathways to protect neurons against alcohol's toxic effects. One signaling pathway that can protect cultured neurons against alcohol-induced cell death in vitro is the cAMP pathway. A goal of this study was to determine whether the cAMP pathway can exert a similar neuroprotective effect against alcohol in vivo. A key molecule within the cAMP pathway is cAMP response element binding protein (CREB). In this study, CREB was specifically disrupted in cerebellar Purkinje cells to study its role in protection of cerebellar neurons against alcohol toxicity.
METHODS
Mice with Purkinje cell-specific knockout of CREB were generated with the Cre-lox system. A 2 × 2 design was used in which Cre-negative and Cre-positive mice received either 0.0 or 2.2 mg/g ethanol by intraperitoneal (i.p.) injection daily over postnatal day (PD) 4-9. Stereological cell counts of cerebellar Purkinje cells and granule cells were performed on PD 10. Motor function was assessed on PD 40 using the rotarod.
RESULTS
Purkinje cell-specific disruption of CREB alone (in the absence of alcohol) induced only a small reduction in Purkinje cell number. However, the loss of CREB function from Purkinje cells greatly increased the vulnerability of Purkinje cells to alcohol-induced cell death. While alcohol killed 20% of Purkinje cells in the Cre-negative (CREB-expressing) mice, alcohol killed 57% of Purkinje cells in the Cre-positive (CREB-nonexpressing) mice. This large loss of Purkinje cells did not lead to similar alcohol-induced losses of granule cells. In the absence of alcohol, lack of CREB function in Purkinje cells had no effect on rotarod performance. However, in the presence of alcohol, disruption of CREB in Purkinje cells substantially worsened rotarod performance.
DISCUSSION
Disruption of a single gene (CREB) in a single neuronal population (Purkinje cells) greatly increases the vulnerability of that cell population to alcohol-induced cell death and worsens alcohol-induced brain dysfunction. The results suggest that the cAMP pathway can protect cells in vivo against alcohol toxicity and underline the importance of genetics in determining the neuropathology and behavioral deficits of FASD.
Topics: Animals; Cerebellum; Cyclic AMP Response Element-Binding Protein; Ethanol; Female; Fetal Alcohol Spectrum Disorders; Humans; Mice; Mice, Knockout; Nitric Oxide Synthase Type I; Pregnancy; Purkinje Cells
PubMed: 35378204
DOI: 10.1016/j.alcohol.2022.02.005 -
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 -
ELife Nov 2018The cerebellum aids the learning of fast, coordinated movements. According to current consensus, erroneously active parallel fibre synapses are depressed by complex...
The cerebellum aids the learning of fast, coordinated movements. According to current consensus, erroneously active parallel fibre synapses are depressed by complex spikes signalling movement errors. However, this theory cannot solve the of processing a global movement evaluation into multiple cell-specific error signals. We identify a possible implementation of an algorithm solving this problem, whereby spontaneous complex spikes perturb ongoing movements, create eligibility traces and signal error changes guiding plasticity. Error changes are extracted by adaptively cancelling the average error. This framework, (SGDEGE), predicts synaptic plasticity rules that apparently contradict the current consensus but were supported by plasticity experiments in slices from mice under conditions designed to be physiological, highlighting the sensitivity of plasticity studies to experimental conditions. We analyse the algorithm's convergence and capacity. Finally, we suggest SGDEGE may also operate in the basal ganglia.
Topics: Action Potentials; Algorithms; Animals; Cerebellum; Computer Simulation; Female; Learning; Long-Term Potentiation; Mice, Inbred C57BL; Neural Networks, Computer; Neuronal Plasticity; Purkinje Cells; Time Factors
PubMed: 30418871
DOI: 10.7554/eLife.31599 -
Neuroscience Letters Jan 2019The genetically heterozygous spinocerebellar ataxias are all characterized by cerebellar atrophy and pervasive Purkinje Cell degeneration. Up to date, more than 35... (Review)
Review
The genetically heterozygous spinocerebellar ataxias are all characterized by cerebellar atrophy and pervasive Purkinje Cell degeneration. Up to date, more than 35 functionally diverse spinocerebellar ataxia genes have been identified. The main question that remains yet unsolved is why do some many genetic insults lead to Purkinje Cell degeneration and spinocerebellar ataxia? To address this question it is important to identify intrinsic pathways important for Purkinje Cell function and survival. In this review, we discuss the current consensus on shared mechanisms underlying the pervasive Purkinje Cell loss in spinocerebellar ataxia. Additionally, using recently published cell type specific expression data, we identified several Purkinje Cell-specific genes and discuss how the corresponding pathways might underlie the vulnerability of Purkinje Cells in response to the diverse genetic insults causing spinocerebellar ataxia.
Topics: Animals; Cerebellum; Humans; Nerve Degeneration; Purkinje Cells; Signal Transduction; Spinocerebellar Ataxias
PubMed: 29421540
DOI: 10.1016/j.neulet.2018.02.004 -
Cerebellum (London, England) Feb 2017Since the last review paper published in Cerebellum in 2002 [1], there has been a substantial increase in the number of experiments utilizing transgenic manipulations in... (Review)
Review
Since the last review paper published in Cerebellum in 2002 [1], there has been a substantial increase in the number of experiments utilizing transgenic manipulations in murine cerebellar Purkinje cells. Most of these approaches were made possible with the use of the Cre/loxP methodology and pcp2/L7 based Cre recombinase expressing transgenic mouse strains. This review aims to summarize all studies which used Purkinje cell specific transgenesis since the first use of mouse strain with Purkinje cell specific Cre expression in 2002.
Topics: Animals; Mice, Transgenic; Models, Animal; Purkinje Cells
PubMed: 26969183
DOI: 10.1007/s12311-016-0770-4 -
Cell Reports May 2023Within the cerebellar cortex, mossy fibers (MFs) excite granule cells (GCs) that excite Purkinje cells (PCs), which provide outputs to the deep cerebellar nuclei (DCNs)....
Within the cerebellar cortex, mossy fibers (MFs) excite granule cells (GCs) that excite Purkinje cells (PCs), which provide outputs to the deep cerebellar nuclei (DCNs). It is well established that PC disruption produces motor deficits such as ataxia. This could arise from either decreases in ongoing PC-DCN inhibition, increases in the variability of PC firing, or disruption of the flow of MF-evoked signals. Remarkably, it is not known whether GCs are essential for normal motor function. Here we address this issue by selectively eliminating calcium channels that mediate transmission (Ca2.1, Ca2.2, and Ca2.3) in a combinatorial manner. We observe profound motor deficits but only when all Ca2 channels are eliminated. In these mice, the baseline rate and variability of PC firing are unaltered, and locomotion-dependent increases in PC firing are eliminated. We conclude that GCs are indispensable for normal motor performance and that disruption of MF-induced signals impairs motor performance.
Topics: Mice; Animals; Cerebellum; Neurons; Purkinje Cells; Cerebellar Cortex; Signal Transduction
PubMed: 37141091
DOI: 10.1016/j.celrep.2023.112429 -
Disease Models & Mechanisms Jun 2024Purkinje cell dysfunction disrupts movement and causes disorders such as ataxia. Recent evidence suggests that Purkinje cell dysfunction may also alter sleep regulation....
Purkinje cell dysfunction disrupts movement and causes disorders such as ataxia. Recent evidence suggests that Purkinje cell dysfunction may also alter sleep regulation. Here, we used an ataxic mouse model generated by silencing Purkinje cell neurotransmission (L7Cre;Vgatfx/fx) to better understand how cerebellar dysfunction impacts sleep physiology. We focused our analysis on sleep architecture and electrocorticography (ECoG) patterns based on their relevance to extracting physiological measurements during sleep. We found that circadian activity was unaltered in the mutant mice, although their sleep parameters and ECoG patterns were modified. The L7Cre;Vgatfx/fx mutant mice had decreased wakefulness and rapid eye movement (REM) sleep, whereas non-REM sleep was increased. The mutants had an extended latency to REM sleep, which is also observed in human patients with ataxia. Spectral analysis of ECoG signals revealed alterations in the power distribution across different frequency bands defining sleep. Therefore, Purkinje cell dysfunction may influence wakefulness and equilibrium of distinct sleep stages in ataxia. Our findings posit a connection between cerebellar dysfunction and disrupted sleep and underscore the importance of examining cerebellar circuit function in sleep disorders.
Topics: Animals; Purkinje Cells; Wakefulness; Ataxia; Sleep; Sleep, REM; Mice; Circadian Rhythm; Disease Models, Animal; Male
PubMed: 38563553
DOI: 10.1242/dmm.050379 -
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