Niswender Laboratory

Current available antipsychotics show efficacy in the treatment of positive symptoms of schizophrenia; however, there remains a substantial need for the treatment of cognitive and negative symptoms. Cognitive deficits are hypothesized to arise from glutamatergic dysfunction, making Group III metabotropic glutamate receptors (mGlu4/7/8) have emerged as promising therapeutic targets due to their potential to restore abnormal glutamatergic signaling. In particular, mGlu7 is widely expressed in the central nervous system and has been linked to cognitive impairments in neuropsychiatric disorders through genetic studies implicating loss-of-function variants in the gene encoding mGlu7, GRM7. Therefore, mGlu7 dysfunction may play a role in the pathophysiology of schizophrenia. My research tests the hypothesis that potentiating mGlu7 through group III agonists and positive allosteric modulators can restore aberrant glutamatergic signaling and improve cognitive function in NMDA receptor hypofunction in vivo models relevant to schizophrenia. Additionally, I am exploring miRNA-based regulation of mGlu7 expression. MicroRNA-34a (miR-34a) has been shown to reduce mGlu7 levels; thus, I aim to design an oligonucleotide that inhibits miR-34a binding to GRM7, thereby enhancing expression in both in vitro and in vivo systems. Both aspects of my project offer a translational approach to address the unmet need for cognitive treatments in schizophrenia.