Karen O’Malley Research Abstract

My laboratory is interested in the molecular and cellular bases of neurological and neuropsychiatric disorders. In particular, we are interested in signal transduction pathways mediated by metabotropic glutamate receptors such as mGluR5. These receptors are widely expressed throughout the CNS and play important roles modulating neuronal excitability during brain and synapse development and in learning and memory. Surprisingly, we found that these receptors are not only expressed on the cell surface but also on nuclear membranes where the mediate unique signaling systems associated with synaptic plasticity. Current efforts are aimed at deducing how receptors are targeted to nuclear membranes and what the long-term consequences of receptor activation are in vivo. Toward this end we have used CRISPR techniques to create transgenic animals expressing mGluR5 only on the cell surface and a separate line of animals expressing mGluR5 only on the nucleus, We plan to use these animals to test the role of intracellular mGlu5 in vivo.

In addition, we have had a longstanding interest in the structure and function of dopamine receptors. We were among the first to isolate D2-like genes (D2, D3, and D4) and to show their unique signaling functions. Recently, we have collaborated with colleagues in Psychiatry exploring associations of these genes with various neurodevelopmental disorders. In particular, variable tandem repeats in the D4 gene have been associated with ADHD, ASD, and schizophrenia (DRD4.7) versus "normal" repeat numbers (DRD4.4). Currently, we are testing newly created humanized DRD4.4 and DRD4.7 humanized mouse lines so as to determine differences in signaling, physiology, and behavior.