The ASPIRE Path in Molecular Medicine

While current antipsychotics effectively treat the positive symptoms of schizophrenia, they offer limited benefit for cognitive and negative symptoms – domains critical to patient functional outcomes. Cognitive deficits are hypothesized to arise from glutamatergic dysfunction, making group III metabotropic glutamate receptors (mGlu4/7/8) promising therapeutic targets due to their potential to restore abnormal glutamatergic signaling. In particular, mGlu7 has been linked to cognitive impairments in neuropsychiatric disorders through genetic studies implicating loss-of-function GRM7 variants, and therefore may play a role in the pathophysiology of schizophrenia. My research tests the hypothesis that activating mGlu7 can restore aberrant glutamatergic signaling and improve cognitive function in NMDA-receptor hypofunction within animal models relevant to schizophrenia. Additionally, I will explore miRNA-based regulation of mGlu7 expression. MicroRNA-34a (miR-34a) has been shown to reduce mGlu7 protein levels; thus, I aim to design an oligonucleotide that inhibits miR-34a binding, thereby enhancing GRM7 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. To ensure the clinical relevance of my work, it is essential to understand how these cognitive symptoms manifest in patients and how novel therapies may impact their quality of life.