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Functional contribution of L-type calcium channels to basolateral amygdala excitability and pathophysiology Zhang, Yiming


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 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.

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