A preclinical therapeutic platform to develop GABAA alpha5 receptor positive allosteric modulators to improve cognitive function in schizophrenia

A preclinical therapeutic platform to develop GABAA α5 receptor positive allosteric modulators to improve cognitive function in schizophrenia. Cognitive dysfunction in neuropsychiatric disorders such as schizophrenia predicts long-term disability and poor patient outcome and is not effectively treated with existing standard-of-care medications. Converging evidence indicates that a primary source of this cognitive impairment is an imbalance in excitatory/inhibitory (E/I) neural responses in critical circuitry for episodic memory. In the medial temporal lobe, weakened inhibition induces an aberrant condition of increased excitation in the hippocampus of individuals with schizophrenia. The aim of this proposal is to develop novel therapeutics to remediate E/I imbalances to improve cognitive function. Using a preclinical platform for drug development, the proposed research is focused on GABAA α5 receptor positive allosteric modulation (PAM) for the treatment of neuropsychiatric conditions characterized by heightened excitation in the hippocampus. The high expression of α5-containing GABAA receptors in the hippocampus, which mediate tonic inhibition, could be ideal for controlling excitation in this circuitry. We will use a series of small molecules with high potency and selectivity for GABAA α5 receptors and PAM activity at the α5 subunit that have met preclinical in vitro and in vivo drug discovery criteria with potential for translational development as therapeutic agents. The current proposed studies will advance this drug development platform to test the efficacy of two GABAA α5 receptor PAMs to improve hippocampal-dependent cognition in a preparation of hippocampal overactivity in rodents. The studies will also assess efficacy by using fiber photometry to monitor neural hyperexcitation in the hippocampal formation during in vivo testing. Together, these studies establish a foundation for a preclinical small molecule drug development program to remediate E/I imbalances underlying cognitive dysfunction in neuropsychiatry.