UBC Theses and Dissertations

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UBC Theses and Dissertations

Functional characterization of T-type calcium channels in area CA3 of the hippocampus Malik, Aqsa


Calcium (Ca²+) entry through voltage-gated Ca²+ channels in dendrites of hippocampal pyramidal cells (PCs) contributes to synaptic depolarization and activation of downstream pathways that regulate many aspects of synaptic and cellular function. Activated by small depolarizing changes in voltage, T-type Ca²+ channels mediate low-threshold spikes (LTS) that drive the resting membrane potential towards action potential threshold. T-type Ca²+ channels are hypothesized to contribute to subthreshold synaptic depolarization in the CA3 subfield of the hippocampus due to the stratified nature of inputs on CA3 dendrites. While T-type Ca²+ channels are densely expressed in area CA3, their functional characteristics and interactions with postsynaptic receptors are not well understood and LTS have not been reported in CA3 PCs. In Chapter 3, using whole-cell electrophysiology, we demonstrate that LTS in CA3 PCs can be evoked by somatic current injection. LTS were only evoked when 4AP was applied to depress A-type K+ channels. Using specific pharmacological blockers, we show that Cav3.2 channels mediate LTS in CA1 and CA3 PCs. In Chapter 4, using two-photon Ca²+ imaging, we map the subcellular distribution of Cav3.2 channels in hippocampal PCs. Our results show that Cav3.2 channel expression is restricted to the soma and proximal dendrites in CA1 PCs, while Ca²+ influx from Cav3.2 channel activation occurs in distal (>50 μm) regions of CA3 PC dendrites. In Chapter 5, we demonstrate that mAChR stimulation potentiates LTS amplitude and such amplification of Ca²+ influx through Cav3.2 channels is dependent on M-current inhibition. Furthermore, we show that application of t-ACPD causes potent and rapid inhibition of LTS propagation. This inhibition occurs exclusively through mGlu₁ receptors and downstream activation of PKC is necessary for this process. Lastly, in Chapter 6, we show boosting of subthreshold synaptic signals by T-type Ca²+ channels in PCs within area CA3 but not CA1. Taken together, our data identify a new T-type mediated Ca²+ signaling pathway in CA3 PC dendrites that is unlocked by A-type K+ channel blockade, potentiated by mAChR activation, and inhibited by mGluR₁ activation. Furthermore, our study highlights the important involvement of T-type Ca²+ channels in enhancing dendritic depolarization in CA3 PCs.

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