Integrated plasticity at inhibitory and excitatory synapses in the cerebellar circuit

The way long-term potentiation (LTP) and depression (LTD) are integrated within the different synapses of brain neuronal circuits is poorly understood. In order to progress beyond the identification of specific molecular mechanisms, a system in which multiple forms of plasticity can be correlated with large-scale neural processing is required. In this paper we take as an example the cerebellar network, in which extensive investigations have revealed LTP and LTD at several excitatory and inhibitory synapses. Cerebellar LTP and LTD occur in all three main cerebellar subcircuits (granular layer, molecular layer, deep cerebellar nuclei) and correspondingly regulate the function of their three main neurons: granule cells (GrCs), Purkinje cells (PCs) and deep cerebellar nuclear (DCN) cells. All these neurons, in addition to be excited, are reached by feed-forward and feed-back inhibitory connections, in which LTP and LTD may either operate synergistically or homeostatically in order to control information flow through the circuit. Although the investigation of individual synaptic plasticities in vitro is essential to prove their existence and mechanisms, it is insufficient to generate a coherent view of their impact on network functioning in vivo. Recent computational models and cell-specific genetic mutations in mice are shedding light on how plasticity at multiple excitatory and inhibitory synapses might regulate neuronal activities in the cerebellar circuit and contribute to learning and memory and behavioral control.This work was supported by European Union grants to ED [CEREBNETFP7-ITN238686, REAL NET FP7-ICT270434, Human Brain Project(HBP-604102)] and by Centro Fermi grant [13(14)] to LM

Modulation, plasticity and pathophysiology of the parallel fiber-purkinje cell synapse

The parallel fiber-Purkinje cell (PF-PC) synapse represents the point of maximal signal divergence in the cerebellar cortex with an estimated number of about 60 billion synaptic contacts in the rat and 100,000 billions in humans. At the same time, the Purkinje cell dendritic tree is a site of remarkable convergence of more than 100,000 parallel fiber synapses. Parallel fiber activity generates fast postsynaptic currents via α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and slower signals, mediated by mGlu1 receptors, resulting in Purkinje cell depolarization accompanied by sharp calcium elevation within dendritic regions. Long-term depression (LTD) and long-term potentiation (LTP) have been widely described for the PF-PC synapse and have been proposed as mechanisms for motor learning. The mechanisms of induction for LTP and LTD involve different signaling mechanisms within the presynaptic terminal and/or at the postsynaptic site, promoting enduring modification in the neurotransmitter release and change in responsiveness to the neurotransmitter. The PF-PC synapse is finely modulated by several neurotransmitters, including serotonin, noradrenaline and acetylcholine. The ability of these neuromodulators to gate LTP and LTD at the PF-PC synapse could, at least in part, explain their effect on cerebellar-dependent learning and memory paradigms. Overall, these findings have important implications for understanding the cerebellar involvement in a series of pathological conditions, ranging from ataxia to autism. For example, PF-PC synapse dysfunctions have been identified in several murine models of spino-cerebellar ataxia (SCA) types 1, 3, 5 and 27. In some cases, the defect is specific for the AMPA receptor signaling (SCA27), while in others the mGlu1 pathway is affected (SCA1, 3, 5). Interestingly, the PF-PC synapse has been shown to be hyper-functional in a mutant mouse model of autism spectrum disorder, with a selective deletion of Pten in Purkinje cells. However, the full range of methodological approaches, that allowed the discovery of the physiological principles of PF-PC synapse function, has not yet been completely exploited to investigate the pathophysiological mechanisms of diseases involving the cerebellum. We, therefore, propose to extend the spectrum of experimental investigations to tackle this problem

Action potential energy efficiency varies among neuron types in vertebrates and invertebrates.

The initiation and propagation of action potentials (APs) places high demands on the energetic resources of neural tissue. Each AP forces ATP-driven ion pumps to work harder to restore the ionic concentration gradients, thus consuming more energy. Here, we ask whether the ionic currents underlying the AP can be predicted theoretically from the principle of minimum energy consumption. A long-held supposition that APs are energetically wasteful, based on theoretical analysis of the squid giant axon AP, has recently been overturned by studies that measured the currents contributing to the AP in several mammalian neurons. In the single compartment models studied here, AP energy consumption varies greatly among vertebrate and invertebrate neurons, with several mammalian neuron models using close to the capacitive minimum of energy needed. Strikingly, energy consumption can increase by more than ten-fold simply by changing the overlap of the Na+ and K+ currents during the AP without changing the APs shape. As a consequence, the height and width of the AP are poor predictors of energy consumption. In the Hodgkin–Huxley model of the squid axon, optimizing the kinetics or number of Na+ and K+ channels can whittle down the number of ATP molecules needed for each AP by a factor of four. In contrast to the squid AP, the temporal profile of the currents underlying APs of some mammalian neurons are nearly perfectly matched to the optimized properties of ionic conductances so as to minimize the ATP cost

소뇌 퍼킨지 세포 내재적 흥분성의 활동-의존적 조절

학위논문 (박사)-- 서울대학교 대학원 : 의과대학 의과학과, 2019. 2. 김상정.Learning rule has been thought to be implemented by activity-dependent modifications of synaptic function and neuronal excitability which contributing to maximization the information flow in the neural network. Since the sensory information is conveyed by forms of action potential (AP) firing, the plasticity of the intrinsic excitability (intrinsic plasticity) has been highlighted the computational feature of the brain. Given the cerebellar Purkinje cells (PCs) is the sole output neurons in the cerebellar cortex, coordination of the synaptic plasticity at the parallel fiber (PF) to PC synapses including long-term depression (LTD) and long-term potentiation (LTP) but also the intrinsic plasticity may play a essential role in information processing in the cerebellum. In this Dissertation, I have investigated several features of intrinsic plasticity in the cerebellar PCs in an activity-dependent manner and their cellular mechanism. Furthermore, the functional implications of the intrinsic plasticity in the cerebellum-dependent behavioral output are discussed. Firstly, I first cover the ion channels regulating the spiking activity of the cerebellar PCs and the cellular mechanisms of the plastic changes in excitability. Various ion channels indeed harmonize the cellular activity and shaping the optimal ranges of the neuronal excitability. Among the ion channels expressed in the cerebellar PCs, hyperpolarization-activated cyclic nucleotide-gated (HCN) channels contribute to the non-Hebbian homeostatic intrinsic plasticity in the cerebellar PCs. Chronic activity-deprivation of PC activity caused the upregulation of agonist-independent activity of type 1 metabotropic glutamate receptor (mGluR1). The increased mGluR1 activity consequently enhanced the HCN channel current density through protein kinase A (PKA) pathway thereby downregulation of intrinsic excitability in PCs. In addition, the intrinsic excitability of PCs is found to be modulated by synaptic activity. Of interest, I investigated that the PF-PC LTD is accompanied by LTD of intrinsic excitability (LTD-IE). The LTD-IE indeed shared intracellular signal cascade for governing the synaptic LTD such as large amount of Ca2+ influx, mGluR1, protein kinase C (PKC) and Ca2+-calmodulin-dependent protein kinase II (CaMKII) activation. Interestingly, the LTD-IE reduced PC spike output without changes in patterns of synaptic integration and spike generation, suggesting that the intrinsic plasticity alters the quantity of information rather than the quality of information processing. In consistent, the LTD-IE was shown in the floccular PCs when the PF-PC LTD occurs. Notably, not only the synaptic LTD but also LTD-IE was found to be formed at the conditioned dendritic branch. Thus, synaptic plasticity could significantly affect to the neuronal net output through the synergistic coordination of synaptic and intrinsic plasticity in the dendrosomatic axis of the cerebellar PCs. In conclusion, the activity-dependent modulation of intrinsic excitability may contribute to dynamic tuning of the cerebellar PC output for appropriate signal transduction into the downstream neurons of the cerebellar PCs.생명체는 끊임없이 주변환경에 반응하여 행동을 수정하며 이러한 적응은 변화하는 환경에서 생존에 필수적이다. 소뇌-운동 학습은 대표적인 적응 행동의 예이다. 다양한 감각 신호들이 소뇌로 전달되어 처리된 후 소뇌 출력을 통해 운동 협응이 이루어진다. 이러한 소뇌-운동 학습 및 소뇌 기능 조절의 세포 생리학적 기전으로 소뇌 퍼킨지 세포의 시냅스 장기저하가 오랫동안 주목받았다. 퍼킨지 세포의 시냅스 장기저하가 나타나지 않는 유전자 변형 동물 모델들에서 소뇌-운동 학습이 정상적으로 일어나지 않는 현상이 관찰되었기 때문에 시냅스 장기저하 이론은 오랜 시간 소뇌-운동 학습의 기전으로 지지 받았다. 하지만 최근 10년 동안의 연구결과는 시냅스 장기저하만으로 소뇌-운동 학습 및 기능 조절을 설명할 수 없다고 반박한다. 특히 소뇌 퍼킨지 세포는 소뇌 피질로 전달된 감각신호를 처리하여 출력을 담당하는 유일한 신경세포이므로 운동 학습 상황에서 소뇌의 출력이 어떻게 조절되는지를 이해하는 것이 중요하게 인식되었다. 감각 신호가 신경 회로 내에서 전달될 때 활동 전압의 형태로 전달되기 때문에 활동 전압의 발생 빈도 및 패턴 조절 양상에 대한 이해는 소뇌 운동 학습의 기전을 밝히는 데에 중요하다. 본 박사학위 논문에서는 먼저 소뇌 퍼킨지 세포의 내재적 흥분성을 조절하는 여러가지 이온 통로들의 특성에 대해 정리하고 더 나아가 내재적 흥분성 가소성의 기전 및 생리학적 의의를 제시하였다. 소뇌 퍼킨지 세포의 흥분성은 활동-의존적 가소성을 보이는데, 시냅스의 활동이 아닌 소뇌 회로 활동성의 장기적인 변화에 대응하여 나타날 수 있다. 소뇌 회로의 활동을 2일 간의 tetrodotoxin (TTX, 1µM) 처리를 통해 저해하였을 때 과분극에 의해 발생하는 내향전류 (Ih) 증가를 통한 소뇌 퍼킨지 세포의 흥분성이 감소되는 것을 전기생리학적 기록을 통해 관찰하였다. 이러한 장기적인 소뇌 회로의 활동성 변화에 의한 퍼킨지 세포의 내재적 흥분성 감소의 세포생리학적 기전으로서 대사성 글루타메이트 수용체의 길항제-비의존적인 활동성 증가 및 그로 인한 PKA의 증가에 의해 발생함을 생화학 및 전기생리학적 방법을 통해 규명하였다. 이처럼 소뇌 퍼킨지 세포의 내재적 흥분성은 소뇌 회로 내에서 역동적으로 조절되어 소뇌 기능을 조절한다. 더 나아가 퍼킨지 세포의 흥분성 조절과 소뇌-기억형성과의 관계성을 검증하기 위해 소뇌-학습의 세포생리학적 기전으로 알려져있는 퍼킨지 세포 시냅스 장기저하 유도 후 흥분성의 변화를 관찰하였다. 흥미롭게도 퍼킨지 세포의 내재적 흥분성 역시 시냅스 가소성과 마찬가지로 평행섬유와 등반섬유의 활성을 통해 가소성을 보이는데 이 흥분성의 가소성은 대사성 글루타메이트 수용체, PKC 그리고 CaMKII와 같은 시냅스 장기 저하를 야기하는 세포 내 신호전달기전을 필요로 한다. 이러한 실험결과를 통해 시냅스 장기저하가 발생할 때 소뇌 퍼킨지 세포의 내재적 흥분성 역시 같이 감소하여 소뇌 운동 시 소뇌 피질의 출력이 크게 감소함을 예상할 수 있다. 실제로 소뇌 퍼킨지 세포의 신경가소성을 유도한 후 평행섬유를 자극하여 나타나는 퍼킨지 세포의 활동 전압 발생 빈도를 측정해 본 결과, 시냅스 장기저하와 흥분성의 장기저하가 함께 발생했을 때에만 소뇌 퍼킨지 세포의 출력이 유의미하게 감소하는 것을 관찰하였다. 특히 퍼킨지 세포의 활동-의존적 흥분성의 가소성은 시냅스 가소성과 마찬가지로 특정 수상돌기 가지 특이적으로 발생함을 관찰하였다. 이를 통해 퍼킨지 세포의 시냅스 가소성과 흥분성 가소성의 유기적인 연합을 통해 소뇌 퍼킨지 세포의 출력신호가 조절되어 소뇌-운동학습을 조절함을 알 수 있다. 결론적으로 본 박사학위 논문의 연구결과들은 소뇌 퍼킨지 세포의 출력은 퍼킨지 세포의 시냅스 가소성 혹은 흥분성의 조절과 비선형관계를 보이며 이러한 시냅스 가소성과 내재적 가소성의 시너지는 소뇌 정보 저장 능력을 극대화하여 소뇌 기능 조절 및 정보저장에 중요한 역할을 담당하고 있음을 제시한다.Preface Abstract General introduction Chapter 1. Summary of the previous literatures and further implication for physiological significance of the intrinsic plasticity in the cerebellar Purkinje cells Summary. 1.1 Ion channels and spiking activity of the cerebellar Purkinje cells 1.1.1 Voltage-gated Na+ channels 1.1.2 Voltage-gated K+ channels and Ca2+-activated K+ channels 1.2 Activity-dependent plasticity of intrinsic excitability through ion channel modulation 1.2.1 Activity-dependent plasticity of intrinsic. excitability through ion channel 1.2.2 Possible mechanisms for LTD-IE. 1.2.3 Upside down: to what extent does bidirectional intrinsic plasticity in. the cerebellar dependent-motor learning do? 1.3 The further implication of intrinsic plasticity in the memory circuits. Chapter 2. Type 1 metabotropic glutamate receptor mediates homeostatic control of intrinsic excitability through hyperpolarization-activated current in cerebellar Purkinje cells Introduction Material and Method Results 2.1 Chronic activity-deprivation reduces intrinsic excitability of the cerebellar. Purkinje cells 35 2.2 Homeostatic intrinsic plasticity of the cerebellar Purkinje cells is mediated activity-dependent modulation of Ih 2.3 Homeostatic intrinsic plasticity of the cerebellar Purkinje cells requires agonist-independent action of mGluR1 2.4 Homeostatic intrinsic plasticity of the cerebellar Purkinje cells is mediated. PKA activity Discussion Chapter 3. Long-Term Depression of Intrinsic Excitability Accompanied by Synaptic Depression in Cerebellar Purkinje Cells Introduction Material and Method Results 3.1 LTD of intrinsic excitability of PC accompanied by PF-PC LTD 3.2 LTD-IE has different developing kinetics from synaptic LTD 3.3 LTD-IE was not reversed by subsequent LTP-IE induction 3.4 The number of recruited synapses were not correlated to the magnitude of the neuronal 3.5 Information processing after LTD induction LTD-IE was not. reversed by subsequent LTP-IE induction 3.6 LTD-IE required the Ca2+-signal but not depended on the Ca2+-activated K+ channels Discussion Chapter 4. Synergies between synaptic depression and intrinsic plasticity of the cerebellar Purkinje cells determining the Purkinje cell output Introduction Material and Method Restuls 4.1 Timing rules of intrinsic plasticity of floccular PCs 87 4.2 Intrinsic plasticity shares intracellular signaling for PF-PC LTD 4.3 Conditioned PF branches contributing to robust reduction of spike output of the PCs 4.4 Sufficient changes in spiking output require both of plasticity, synaptic and. intrinsic plasticity 4.5 Supralinearity of spiking output coordination after induction of PC plasticity Discussion Bibliography Abstract in Korean AcknowledgementDocto

Astrocytes differentially respond to inflammatory autoimmune insults and imbalances of neural activity

BACKGROUND: Neuronal activity intimately communicates with blood flow through the blood–brain barrier (BBB) in the central nervous system (CNS). Astrocyte endfeet cover more than 90% of brain capillaries and interact with synapses and nodes of Ranvier. The roles of astrocytes in neurovascular coupling in the CNS remain poorly understood. RESULTS: Here we show that astrocytes that are intrinsically different are activated by inflammatory autoimmune insults and alterations of neuronal activity. In the progression of experimental autoimmune encephalomyelitis (EAE), both fibrous and protoplasmic astrocytes were broadly and reversibly activated in the brain and spinal cord, indicated by marked upregulation of glial fibrillary acidic protein (GFAP) and other astrocytic proteins. In early and remitting EAE, upregulated GFAP and astrocytic endfoot water channel aquaporin 4 (AQP4) enclosed white matter lesions in spinal cord, whereas they markedly increased and formed bundles in exacerbated lesions in late EAE. In cerebellar cortex, upregulation of astrocytic proteins correlated with EAE severity. On the other hand, protoplasmic astrocytes were also markedly activated in the brains of ankyrin-G (AnkG) and Kv3.1 KO mice, where neuronal activities are altered. Massive astrocytes replaced degenerated Purkinje neurons in AnkG KO mice. In Kv3.1 KO mice, GFAP staining significantly increased in cerebellar cortex, where Kv3.1 is normally highly expressed, but displayed in a patchy pattern in parts of the hippocampus. CONCLUSIONS: Thus, astrocytes can detect changes in both blood and neurons, which supports their central role in neurovascular coupling. These studies contribute to the development of new strategies of neuroprotection and repair for various diseases, through activity-dependent regulation of neurovascular coupling

Defining and modeling known adverse outcome pathways: Domoic acid and neuronal signaling as a case study

An adverse outcome pathway (AOP) is a sequence of key events from a molecular-level initiating event and an ensuing cascade of steps to an adverse outcome with population-level significance. To implement a predictive strategy for ecotoxicology, the multiscale nature of an AOP requires computational models to link salient processes (e.g., in chemical uptake, toxicokinetics, toxicodynamics, and population dynamics). A case study with domoic acid was used to demonstrate strategies and enable generic recommendations for developing computational models in an effort to move toward a toxicity testing paradigm focused on toxicity pathway perturbations applicable to ecological risk assessment. Domoic acid, an algal toxin with adverse effects on both wildlife and humans, is a potent agonist for kainate receptors (ionotropic glutamate receptors whose activation leads to the influx of Na + and Ca 2+ ). Increased Ca 2+ concentrations result in neuronal excitotoxicity and cell death, primarily in the hippocampus, which produces seizures, impairs learning and memory, and alters behavior in some species. Altered neuronal Ca 2+ is a key process in domoic acid toxicity, which can be evaluated in vitro. Furthermore, results of these assays would be amenable to mechanistic modeling for identifying domoic acid concentrations and Ca 2+ perturbations that are normal, adaptive, or clearly toxic. In vitro assays with outputs amenable to measurement in exposed populations can link in vitro to in vivo conditions, and toxicokinetic information will aid in linking in vitro results to the individual organism. Development of an AOP required an iterative process with three important outcomes: a critically reviewed, stressor-specific AOP; identification of key processes suitable for evaluation with in vitro assays; and strategies for model development. Environ. Toxicol. Chem. 2011;30:9–21. © 2010 SETACPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78481/1/373_ftp.pd

Rôle de deux groupes de vésicules dans la transmission synaptique

Les synapses formées par les fibres moussues (FM) sur les cellules principales de la région CA3 (FM-CA3) jouent un rôle crucial pour la formation de la mémoire spatiale dans l’hippocampe. Une caractéristique des FM est la grande quantité de zinc localisée avec le glutamate dans les vésicules synaptiques recyclées par la voie d’endocytose dépendante de l’AP3. En combinant l’imagerie calcique et l’électrophysiologie, nous avons étudié le rôle des vésicules contenant le zinc dans la neurotransmission aux synapses FM-CA3. Contrairement aux études précédentes, nous n’avons pas observé de rôle pour le zinc dans l’induction des vagues calciques. Nos expériences ont révélé que les vagues calciques sont dépendantes de l’activation des récepteurs métabotropiques et ionotropiques du glutamate. D’autre part, nos données indiquent que les vésicules dérivées de la voie dépendante de l’AP3 forment un groupe de vésicules possédant des propriétés spécifiques. Elles contribuent principalement au relâchement asynchrone du glutamate. Ainsi, les cellules principales du CA3 de souris n’exprimant pas la protéine AP3 avaient une probabilité inférieure de décharge et une réduction de la synchronie des potentiels d’action lors de la stimulation à fréquences physiologiques. Cette diminution de la synchronie n’était pas associée avec un changement des paramètres quantiques ou de la taille des groupes de vésicules. Ces résultats supportent l’hypothèse que deux groupes de vésicules sont présents dans le même bouton synaptique. Le premier groupe est composé de vésicules recyclées par la voie d’endocytose utilisant la clathrine et participe au relâchement synchrone du glutamate. Le second groupe est constitué de vésicules ayant été recyclées par la voie d’endocytose dépendante de l’AP3 et contribue au relâchement asynchrone du glutamate. Ces deux groupes de vésicules sont nécessaires pour l’encodage de l’information et pourraient être importants pour la formation de la mémoire. Ainsi, les décharges de courte durée à haute fréquence observées lorsque les animaux pénètrent dans les places fields pourraient causer le relâchement asynchrone de glutamate. Finalement, les résultats de mon projet de doctorat valident l’existence et l’importance de deux groupes de vésicules dans les MF qui sont recyclées par des voies d’endocytoses distinctes et relâchées durant différents types d’activités.Mossy fiber-CA3 pyramidal cell synapses play a crucial role in the hippocampal formation of spatial memories. These synaptic connections possess a number of unique features substantial for its role in the information processing and coding. One of these features is presence of zinc co-localized with glutamate within a subpopulation of synaptic vesicles recycling through AP3-dependent bulk endocytosis. Using Ca2+ imaging and electrophysiological recordings we investigated role of these zinc containing vesicles in the neurotransmission. In contrast to previous reports, we did not observe any significant role of vesicular zinc in the induction of large postsynaptic Ca2+ waves triggered by burst stimulation. Moreover, our experiments revealed that Ca2+ waves mediated by Ca2+ release from internal stores are dependent not only on the activation of metabotropic, but also ionotropic glutamate receptors. Nevertheless, subsequent experiments unveiled that the vesicles derived via AP3-dependent endocytosis primary contribute to the asynchronous, but not synchronous mode of glutamate release. Futhermore, knockout mice lacking adaptor protein AP3 had a reduced synchronization of postsynaptic action potentials and impaired information transfer; this was not associated with any changes in the synchronous release quantal parameters and vesicle pool size. These findings strongly support the idea that within a single presynaptic bouton two heterogeneous pools of releasable vesicles are present. One pool of readily releasable vesicles forms via clathrin mediated endocytosis and mainly participates in the synchronous release; a second pool forms through bulk endocytosis and primarily supplies asynchronous release. The existence of two specialized pools is essential for the information coding and transfer within hippocampus. It also might be important for hippocampal memory formation. In contrast to low firing rates at rest, dentate gyrus granule cells tend to fire high frequency bursts once an animal enters a place field. These burst activities, embedded in the lower gamma frequency, should be especially efficient in the triggering of substantial asynchronous glutamate release. Therefore, the results of my PhD project for the first time provide strong evidence for the presence and physiological importance of two vesicle pools with heterogeneous release and recycling properties via separate endocytic pathways within the same mossy fiber bouton

Dendritic Excitability and Protein Kinase C Activity Regulate Purkinje Neuron Dendrite Degeneration in Cerebellar Ataxia

Spinocerebellar ataxias (SCAs) are hereditary neurodegenerative disorders that are united by their autosomal dominant inheritance and their common clinical feature: cerebellar ataxia. Cerebellar ataxia is a disorder of impaired motor coordination, and in many SCAs the cause of degraded motor coordination is understood to be degeneration of cerebellar Purkinje neurons. The degeneration of Purkinje neurons in many SCAs is thought to progress from degeneration of the elaborate Purkinje neuron dendrite arbor to eventual cell death. Although it is likely that the early dendrite degeneration contributes substantially to motor impairment, the cellular processes which drive dendrite degeneration remain very poorly understood. It is known that synaptic inputs and intrinsic excitability shape Purkinje neuron dendrites during development, and several studies in different SCA models have suggested that altered synaptic input or action potential firing contributes to Purkinje neuron degeneration. Not yet explored in any of the SCA models is whether the physiology of the Purkinje neuron dendritic shaft are altered. In a mouse model of spinocerebellar ataxia type 1 (SCA1), we tested the hypothesis that SCA1 Purkinje neurons would show an increase in intrinsic dendritic excitability that promotes dendrite degeneration. Our studies identified an increase in intrinsic dendritic excitability throughout the course of dendritic degeneration, and we showed that this increased dendritic excitability was associated with changes in expression of several channels that regulate dendritic excitability. Subsequently, we demonstrated that normalizing dendritic excitability exerts a dendro-protective effect in SCA1 Purkinje neurons, supporting the hypothesis that increased intrinsic dendritic excitability drives SCA1 Purkinje neuron dendrite degeneration. In our attempts to uncover the pathway(s) by which increased dendritic excitability drives SCA1 Purkinje neuron dendrite degeneration, we uncovered a large increase in phosphorylation of protein kinase C (PKC) enzyme targets in SCA1 mice and SCA1 patient tissue. PKC activity is an important regulator of Purkinje neuron dendritic structure, and we hypothesized that increased PKC activity downstream of increased excitability promotes dendritic degeneration. Surprisingly, suppression of PKC activity in SCA1 mice resulted in accelerated dendritic degeneration, suggesting that the increased PKC activation is dendro-protective. A similar dendro-protective effect was observed in a model of a different cerebellar ataxia, Spinocerebellar ataxia type 2 (SCA2). Studies from the SCA1 mice suggest that PKC enzymes may be exerting their dendro-protective effect by counteracting (although incompletely) increases in dendritic excitability, further supporting the role that dendritic excitability plays as a driver of Purkinje neuron dendritic degeneration. This thesis establishes both intrinsic dendritic excitability and PKC activity as important regulators of Purkinje neuron dendrite degeneration in SCA1 and beyond. The results provide clinically-relevant therapeutic targets, and also provide a novel conceptual framework for understanding Purkinje neuron dendrite remodeling in health and disease. Together, these findings establish that Purkinje neuron dendrite degeneration is in fact a regulated process, with dendrite excitability and PKC activity specifically identified as two key regulators of that process.PHDNeuroscience PhDUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/155146/1/chopravi_1.pd