Funding tool: Basic research projects
Project-ID: LS19-017
Project start: 01. Jänner 2021
Project end: will follow
Runtime: 36 months / ongoing
Funding amount: € 290.000,00

Brief summary:

Within the EU more than 3 million people suffer from autism and more than 5 million from schizophrenia. However, disease mechanisms are still poorly understood. Over the last 20 years ?2? subunits of voltage-gated calcium channels have emerged as major drug targets. The anti-allodynic and anti-epileptic drugs gabapentin and pregabalin are currently the top sold anti-epileptic drugs and are particularly prescribed for neuropathic pain conditions. Three different types of ?2? subunits are expressed in the brain and their overall importance is emphasized by their involvement in various neurological disorders: ?2?-1 and ?2?-2 have been linked to epilepsy, ?2?-1 and ?2?-3 are potential risk genes for autism spectrum disorders and all three genes may be associated with schizophrenia. Despite these prominent roles, surprisingly little is known about the specific functions of ?2? subunits. We have recently identified a particular role of ?2?-2 in the axonal wiring of inhibitory GABAergic synapses. In excitatory synapses, on the other hand, ?2? subunits share redundant functions in excitatory synapse formation. Progress in analyzing specific roles of individual ?2? subunits and their contribution to neuropsychiatric disorders is limited by the lack of suitable model systems. For example, all existing classical knockout or mutant mice for ?2? isoforms suffer from confounding peripheral diseases including cardiovascular diseases, diabetes or altered sensory processing. To overcome this limitation we here plan establishing conditional (floxed) mouse models for all neuronal ?2? subunits. Cross-breeding of mice will allow the generation of double and, ultimately, triple floxed mice. Importantly, these mice can be bred and propagated without any disease phenotype and the knockout condition can be specifically induced in cultured neurons, enabling the in vitro analysis of cellular and synaptic functions. Thus, we are planning establishing ?2? subunit triple knockout cultured neurons as powerful tool for quantitatively analyzing synaptic functions of the distinct subunit types in vitro. Finally, generation of conditional knockout mice will provide novel mouse models for the future analysis of the yet unknown role of ?2? subunits in neuropsychiatric disorders such as autism or schizophrenia. The present proposal combines the expertise of two rather new research facilities in Lower Austria, the IST Austria in Klosterneuburg and the Karl Landsteiner University in Krems. A young talented scientist at the University of Innsbruck, who will support the knowledge transfer on sophisticated neuronal cell culture systems, complements the project team. The grant proposal further utilizes state-of-the-art core-facility instrumentation recently implemented at the Campus Krems. The present proposal will strengthen Lower Austria as a center for neuroscience research and provide newly developed tools to international collaborators for future joint projects.

Keywords:
Physiology, Pharmacology, Cell Biology