Perspectives on Neuroscience and Behavior.

Schizophrenia (SZ) and bipolar disorder (BPD) have many common clinical features and they have shared polygenetic risks. An improved understanding of the common neurobiological pathways involved would be an important advance. Now, this has been accomplished in an outstanding study where it was found that SZ and BPD have upregulation of miR-124-3p in olfactory epithelium derived neuronal cells and postmortem prefrontal cortex, and that this was associated with shared polygenetic risks of the two disorders. In a mouse model with upregulation of miR-124-3p in the medial prefrontal cortex (mPFC) there was increased GRIA2lacking calcium-permeable AMPA receptors (AMPARs) and the mice had impaired social interaction and increased sensitivity to amphetamine. The increase in GRIA2 lacking calcium-permeable AMPARs increased the post-synaptic conductance of AMPARs and miniature excitatory postsynaptic currents (mESPC) amplitude. The selective antagonism of GRIA2-lacking calcium-permeable AMPARs by Naspm normalized the increased amplitude of mESPCs, and local infusion of Naspm into the mPFC reduced the behavioral deficits in social interaction and amphetamine sensitivity. Adeno-associated virus mediated expression of GRIA2 in mouse prefrontal cortex excitatory neurons reduced the behavioral defects (Namkung and others 2023). This article is an outstanding example of how the focus on neurobiological mechanisms underlying behavioral dimensions can improve our understanding of key biological pathways involved in the pathogenesis of behavioral abnormalities. This in turn provides new opportunities for the development of more efficacious therapeutic interventions.