T-type CaV3.2 calcium channels are widely expressed in various types of neurons and dysfunction of CaV3.2 channels has been strongly implicated in human childhood absence epilepsy (CAE). However, the role of these calcium channels in neurons remains unknown. More surprisingly, ~50% CAE patients did not respond to ethosuximide, a T-type Ca2+ channel antagonist and first-line drug used to treat CAE, and most of the nonresponsive patients carry gain-of-function Cav3.2 mutations. In this project, we plan to investigate the functional role of CaV3.2 channels in neuronal cells and the pathogenesis of ~20 CAE-linked human CaV3.2 channel mutations. In the preliminary investigation, we manipulated the activity of CaV3.2 channels genetically and pharmacologically, and monitored the effects with electrophysiological, two-photon imaging, electron microscopic and behavioral analyses. Our preliminary results consistently show that unlike other calcium channels, CaV3.2 channels function primarily to regulate NMDA-R-mediated transmission at synapses. Therefore, we hypothesize that CaV3.2 channels regulate synaptic NMDA transmission and that CAE- linked CaV3.2 channel mutations enhance susceptibility to absence seizures by potentiating glutamatergic transmission. Specifically, we will examine whether the activity of CaV3.2 channels enhances NMDA and AMPA responses in multiple different types of rat neurons in vitro and in vivo (Aim 1a). Moreover, we plan to study whether CaV3.2 channel activity-coupled synaptic calcium influx enhances NMDA responses that lead to the secondary potentiation of AMPA responses (Aim 1b). These results will define that the primary physiological function of neuronal CaV3.2 channels is to regulate glutamatergic synaptic transmission. In addition, we will examine how each of ~20 CAE- linked human CaV3.2 mutations may affect synaptic glutamatergic transmission (Aim 2a). Finally, we plan to investigate whether each of ~20 CAE-linked human CaV3.2 mutations may enhance the susceptibility to 2-4 Hz spike-and-wave discharges and absence-like seizures and if the seizures can be suppressed by glutamate receptor antagonists (Aim 2b). These results will shed new light on the mechanism and suggest new intervention for human CaV3.2 mutation-associated CAE.

Public Health Relevance

T-type CaV3.2 calcium channels are widely expressed in various types of neurons and strongly implicated in human childhood absence epilepsy (CAE), yet the role of neuronal CaV3.2 channels in physiological and pathological conditions remains unclear. This project aims to understand the physiological role of CaV3.2 channels in neuronal cells and neuropathy of CAE-linked human CaV3.2 channel mutations.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Whittemore, Vicky R
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University of Virginia
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Zhang, Lei; Zhang, Peng; Wang, Guangfu et al. (2018) Ras and Rap Signal Bidirectional Synaptic Plasticity via Distinct Subcellular Microdomains. Neuron 98:783-800.e4
Jing, Miao; Zhang, Peng; Wang, Guangfu et al. (2018) A genetically encoded fluorescent acetylcholine indicator for in vitro and in vivo studies. Nat Biotechnol 36:726-737
Lim, Chae-Seok; Kang, Xi; Mirabella, Vincent et al. (2017) BRaf signaling principles unveiled by large-scale human mutation analysis with a rapid lentivirus-based gene replacement method. Genes Dev 31:537-552
Lim, Chae-Seok; Wen, Cheng; Sheng, Yanghui et al. (2017) Piconewton-Scale Analysis of Ras-BRaf Signal Transduction with Single-Molecule Force Spectroscopy. Small 13:
Wang, Yiqing; Zhang, Peng; Wyskiel, Daniel R (2016) Chandelier Cells in Functional and Dysfunctional Neural Circuits. Front Neural Circuits 10:33
Sheng, Yanghui; Zhang, Lei; Su, Susan C et al. (2016) Cdk5 is a New Rapid Synaptic Homeostasis Regulator Capable of Initiating the Early Alzheimer-Like Pathology. Cereb Cortex 26:2937-51
Dalla Massara, Lorenza; Osuru, Hari Prasad; Oklopcic, Azra et al. (2016) General Anesthesia Causes Epigenetic Histone Modulation of c-Fos and Brain-derived Neurotrophic Factor, Target Genes Important for Neuronal Development in the Immature Rat Hippocampus. Anesthesiology 124:1311-1327
Wang, Guangfu; Wyskiel, Daniel R; Yang, Weiguo et al. (2015) An optogenetics- and imaging-assisted simultaneous multiple patch-clamp recording system for decoding complex neural circuits. Nat Protoc 10:397-412
Guo, Weixiang; Polich, Eric D; Su, Juan et al. (2015) Fragile X Proteins FMRP and FXR2P Control Synaptic GluA1 Expression and Neuronal Maturation via Distinct Mechanisms. Cell Rep 11:1651-66
Wang, Guangfu; Bochorishvili, Genrieta; Chen, Yucai et al. (2015) CaV3.2 calcium channels control NMDA receptor-mediated transmission: a new mechanism for absence epilepsy. Genes Dev 29:1535-51

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