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Download The FUNCTIONAL CONTRIBUTIONS OF L-TYPE CALCIUM CHANNELS TO BASOLATERAL AMYGDALA EXCITABILITY AND PATHOPHYSIOLOGY by Yiming Zhang B.Sc., Henan Agricultural University, China, 2009 M.Sc., Soochow University, China, 2012 A DISSERTATION SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in The Faculty of Graduate and Postdoctoral Studies (Neuroscience) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) December 2020 © Yiming Zhang, 2020 The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Functional contributions of L-type calcium channels to basolateral amgydala excitability and pathophysiology Submitted by Yiming Zhang in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Neuroscience Examining Committee: Terrance P. Snutch, Neuroscience, UBC Supervisor Brian MacVicar, Neuroscience, UBC Supervisory Committee Member Anthony Phillips, Psychiatry, UBC University Examiner Filip Van Petegem, Biochemistry, UBC University Examiner Additional Supervisory Committee Memmbers: Shernaz Bamji, Cellular and Physiological Sciences, UBC Supervisory Committee Member Yu-Tian Wang, Neurology, UBC Supervisory Committee Member ii Abstract Calcium influx via neuronal L-type calcium channels (LTCCs) has been implicated in regulating activity-dependent gene transcription, synaptic plasticity, and synaptogenesis. While gain-of-function mutations in neuronal LTCCs have been linked to neurodevelopmental diseases, including autism spectrum disorders (ASDs), the role of LTCCs in regulating neuronal electrophysiological properties during early development remains unclear. The amygdala complex contributes toward emotional processes such as fear, anxiety and social cognition and studies suggest that increased excitability of basolateral amygdala (BLA) principal neurons underlie certain neuropsychiatric disorders. While LTCCs are expressed throughout the BLA, direct evidence for increased LTCC activity affecting BLA excitability and potentially contributing to disease pathophysiology is lacking. In Chapter Ⅰ of my study I investigated the contributions of LTCCs to the excitability and synaptic activity of BLA principal neurons at early developmental stages (postnatal day 7 (P7) and P21). By directly applying LTCC agonist (S)-Bay K8644 (BayK) onto brain slices, I found that BLA principal neurons displayed distinct alterations between P7 and P21 in intrinsic excitability properties, including firing frequency response, spike- frequency adaptation and altered spontaneous neurotransmission. These results suggested the possibility that the functional increase of LTCC activity at different stages of neurodevelopment may lead to alterations to BLA neuronal network activity. To investigate the effects of increased LTCC activity as it might relate to the underlying mechanism of developmental disorders such as ASD, in Chapter Ⅱ I examined the effects of increased LTCC function in early development on long-lasting neuronal excitability, synaptic plasticity and behavioral phenotypes. Bilateral injection of BayK into the BLA at different early stages (P7 or P14) followed by recovery and testing at P28 showed enhanced BLA neuronal excitability, long-term potentiation, as well as altered social behaviors, anxiety and repetitive behaviors. Whereas P28 animals that received BayK injection at P21 did not iii display any differences compared to DMSO control. These results provide evidence for the contributions of LTCCs at different stages of neurodevelopment, as well as their role in inducing long-lasting alterations in neuronal networks and behavioral phenotypes. They also provide new insights into LTCC dysfunction as it is potentially related to amygdala- related neurological disorders. iv Lay Summary L-type calcium channels (LTCCs) are a group of proteins that selectively mediate calcium influx across the cellular membrane. Calcium ions then regulate multiple cellular functions. LTCCs are abundant in the basolateral amygdala (BLA), a brain region involved in social engagement. Morphological and functional changes of the BLA contribute to the impairment of social interaction abilities associated with autism. To date, the potential contributions of LTCCs in BLA neuronal function and networks in physiological or pathological conditions are unclear. In my study using rats, I first found that the functional increase in LTCC activity differentially modified the electrical properties of BLA neurons at different ages of early development. In addition, by inducing LTCC enhancement at early ages after birth I found resulting long-lasting changes in BLA neuronal functions and in animal behavioral traits. The results provide a new approach towards understanding the mechanisms of LTCC dysfunction in neurodevelopmental disorders. v Preface The dissertation is an original interllectual product of the author, Yiming Zhang. All of the work presented was conducted in the Michael Smith Laboratories and the Centre for Brain Health at the University of British Columbia, Point Grey campus. A version of Chapter 1 has been published: Zhang Y, Garcia E, Sack A-S & Snutch TP (2020). L-type calcium channel contributions to intrinsic excitability and synaptic activity during basolateral amygdala postnatal development. Journal of Neurophysiology 123, 1216–1235. vi Table of Contents Abstract ............................................................................................................................. iii Lay Summary .................................................................................................................... v Preface ............................................................................................................................... vi Table of Contents ............................................................................................................ vii List of Tables ...................................................................................................................... x List of Figures ................................................................................................................... xi List of Abbreviations ...................................................................................................... xiv Acknowledgements ........................................................................................................ xvi 1 Introduction .................................................................................................................... 1 1.1 Voltage-gated calcium channels ........................................................................ 1 1.1.1 VGCC structure and functional domains ...................................................................... 1 1.1.2 Alternative splicing in VGCCs ............................................................................................ 6 1.1.3 VGCC Distribution and functional relevance of VGCC ................................................ 10 1.1.3.1 Cav1 family .................................................................................................................. 10 1.1.3.1 Cav2 family .................................................................................................................. 10 1.1.3.3 Cav3 family .................................................................................................................. 14 1.2 Neuronal L-type calcium channels ................................................................. 20 1.2.1 Pharmacological ligands of LTCCs .............................................................................. 20 1.2.2 Biological functions of neuronal LTCCs .......................................................................... 23 1.2.2 Distinct contributions of Cav1.2 and Cav1.3 to neuronal function ............................ 25 1.2.4 LTCC neuronal channelopathies ...................................................................................... 27 1.3 Cav1 channels and Autism Spectrum Disorders ........................................... 35 1.3.1 Genetic factors related to ASD ...................................................................................... 36 1.3.2 Animal Models of ASD ................................................................................................... 39 1.4 Brain regions associated with ASD; involvement of the basolateral amygdala 47 1.5 Thesis Objectives .............................................................................................. 53 2 CHAPTERⅠ: Contribution of L-type calcium channels to firing activity in the rat basolateral amygdala at different stages of postnatal development ..................... 55 vii 2.1 Intruduction ...................................................................................................... 55 2.2 Methods .................................................................................................................. 58 2.3 Results ..................................................................................................................... 63 2.3.1 Enhancement of L-type channels differentially regulates intrinsic membrane properties of immature and juvenile BLA neurons. ................................................................................... 63 2.3.2 Increase of L-type calcium channel activity reduces spike frequency adaptation of P7 BLA neurons. ..............................................................................................................................
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