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We are delighted to host Dr. Gerald Obermair, a well-known neuroscientist from Karl Landsteiner University, Krems, Austria who will be visiting on Thursday, July 31.
Seminar summary:
Voltage-gated calcium channels (VGCCs) are essential regulators of cellular excitability and synaptic communication. Among their auxiliary subunits, the α2δ proteins play a pivotal role in regulating channel expression, biophysical properties, and synaptic functions. Clinically, α2δ proteins are the target of gabapentinoids, Gabapentin and Pregabalin, therapeutics use in the treatment of neuropathic pain, restless leg syndrome, epilepsy and generalized anxiety disorder. This presentation focuses on the presynaptic functions of α2δ proteins, particularly α2δ-2 and α2δ-3, and presents insights into their role in neurodevelopmental and neuropsychiatric disorders.
Experimental data from knockout and rescue models reveal that α2δ proteins are key organizers of excitatory glutamatergic synapses, with highly redundant roles across isoforms. Presynaptic expression of a specific α2δ-2 splice variant modulates postsynaptic GABA receptor abundance and synaptic wiring, independent of the interaction with calcium channels. Mutations in CACNA2D genes are linked to a spectrum of disorders including epileptic encephalopathy, autism, and schizophrenia. Functional analyses of specific mutations (e.g., R596P and G303V in α2δ-2) demonstrate altered calcium signaling, impaired synaptic targeting, and disrupted trans-synaptic communication. Moreover, behavioral and electrophysiological studies in α2δ-3 knockout mice further support the role of α2δ proteins in shaping neuronal connectivity and plasticity.
These findings underscore the dual role of α2δ proteins in channel-dependent and independent mechanisms, highlighting their contribution to both channelopathies and synaptopathies. Understanding these pathways offers promising avenues for future therapeutic intervention in neurodevelopmental disorders.