The role of CaV3.1 T-type calcium channels in cognitive functions mediated by the subicular circuitry

摘要

Abstract Cognitive deficits associated with multiple psychiatric disorders appear to emerge as a consequence of changes in synaptic plasticity and neuronal oscillations of the subiculum, the main output structure of the hippocampal formation. Thus, resolving the mechanisms that regulate subicular network activity is a crucial task in the pursuit of novel treatment targets. The majority of subicular neurons can generate high-frequency burst firing which, along with their ideal anatomical location, enable them to serve as a relay center between the hippocampal formation and cortical structures, most notably the medial prefrontal cortex (mPFC). This tendency of subicular pyramidal neurons to burst in rhythmic patterns is likely to be critical for processing important cognitive information. However, ionic currents that regulate the excitability and, consequently, the function of the subicular network are largely unknown. Low-voltage activated T-type calcium channels (T-channels) are ideally suited for modulation of neuronal excitability and oscillatory activity. The preliminary patch-clamp data in mice with global knock-out of CACNA1G (CaV3.1) strongly suggest a crucial role of this T-channel isoform in mediating excitability of subicular burst firing neurons. Moreover, the lack of CaV3.1 T-channels induces a complete loss of long-term potentiation (LTP), the best cellular model of memory processing, at the CA1-subiculum synapse. Finally, the decrease in the power of high-frequency (gamma) oscillations in freely moving CaV3.1 KO mice is accompanied by impairment of spatial navigation, which was confirmed with the subiculum-specific CACNA1G knock-down. Therefore, the central hypothesis of this proposal is that CaV3.1 T-channels, by supporting burst firing, regulate synaptic plasticity and neuronal oscillations in the subiculum, as well as its input to mPFC, thereby modulating cognitive processing. During the K01 award, three research aims will be evaluated: 1) to investigate whether CaV3.1 T-channels regulate synaptic plasticity in the subiculum using ex vivo slice preparation, 2) to investigate whether subicular CaV3.1 T-channels are important for learning and memory in vivo using tissue-specific knock- down and selective pharmacology, and 3) to investigate whether CaV3.1 T-channels regulate high-frequency oscillations in the subiculum and neuronal synchronization between the subiculum and mPFC during a behavioral memory task. To meet his career objectives and the aims of this research project, the applicant requires additional training in viral-mediated genetic manipulations, in vitro (LTP) and in vivo local field potential, as well as single-unit recordings. These experiments will provide valuable insights into the function of T-channels in a specific subicular circuit and underlying neuronal oscillations associated with cognitive processing. By complementing the applicant’s present expertise in behavioral pharmacology and patch-clamp electrophysiology with the training in synaptic plasticity and sophisticated in vivo electrophysiological methods, this research proposal will build the foundation for the applicant’s future research in animal models of psychiatric disorders.