T-type calcium channel Cav3.2 modulates dentate gyrus granule cell excitability and plasticity in a maturational stage dependent manner

Throughout the brain, calcium influx via low-threshold-activated T-type calcium channels shapes neuronal excitability and plasticity contributing to numerous physiological functions such as sleep and nociception. Under pathophysiological conditions, T-type calcium channels can also impart aberrant neuronal excitability, contributing to disorders such as epilepsy. The T-type channel subtype Cav3.2 is highly expressed in the dentate gyrus (DG) of the hippocampus and mice lacking Cav3.2 (KO) exhibit impairments in hippocampal dependent learning and memory tasks, as well as attenuated development of pilocarpine induced temporal lobe epilepsy. As a result of ongoing neurogenesis, DG granule cells (GCs) are a heterogenous population with varying degrees of maturation. Throughout their maturation, GC morphology and expression of ion channels develops, altering their intrinsic excitability. While initial studies identified a role for Cav3.2 channels in the excitability of mature DG GCs, their functional relevance to the intrinsic excitability and plasticity of different GC subpopulations has not yet been examined. Using Cav3.2 knockout (KO) mice, I first examined how loss of Cav3.2 channels alters both GC intrinsic excitability and the processing of frequency-dependent inputs in subpopulations of GCs. Loss of Cav3.2 channels impacted firing patterns characteristic of GCs maturational stages, reducing low-threshold calcium spikes in immature GCs and regulating firing frequency as GCs matured. I further explored how these maturational dependent effects on intrinsic excitability impact the DG circuit by examining synaptic activity and plasticity at the medial perforant path synapse. Loss of Cav3.2 channels impaired synaptic plasticity, leading to reduced post-tetanic potentiation following theta-based stimulation. Together, these results identify Cav3.2 channels as key regulators of GC excitability and plasticity that emerge early in their maturation. Calcium influx via Cav3.2 channels is therefore predicted to have maturation-dependent contributions to DG processes including GC survival, integration and excitability, relevant for physiological functions such as learning and memory as well as pathological processes including acquired temporal lobe epilepsy.