CRISPR-Cas9-Mediated Intersectional Knockout of Glycogen Synthase Kinase 3? in D2 Receptor-Expressing Medial Prefrontal Cortex Neurons Reveals Contributions to Emotional Regulation.

ABSTRACT: Glycogen synthase kinase 3? (GSK3?) activity is regulated by dopamine D2 receptor signaling and can be inhibited by psychoactive drugs in a D2 receptor-dependent manner. However, GSK3? is ubiquitously expressed in the brain, and D2 receptor-expressing cells are distributed as a mosaic in multiple cortical regions. This complicates the interrogation of GSK3? functions in cortical D2 cells in a circuit-defined manner using conventional animal models. We used a CRISPR-Cas9-mediated intersectional approach to achieve targeted deletion of GSK3? in D2-expressing neurons of the adult medial prefrontal cortex (mPFC). Isolation and analysis of ribosome-associated RNA specifically from mPFC D2 neurons lacking GSK3? demonstrated large-scale translatome alterations. Deletion of GSK3? in mPFC D2 neurons revealed its contribution to anxiety-related, cognitive, and social behaviors. Our results underscore the viability of an intersectional knockout approach to study functions of a ubiquitous gene in a network-defined fashion while uncovering the contribution of GSK3? expressed in mPFC D2 neurons in the regulation of behavioral dimensions related to mood and emotions. This advances our understanding of GSK3? action at a brain circuit level and can potentially lead to the development of circuit selective therapeutics.

SUBMITTER: Khlghatyan J 

PROVIDER: S-EPMC7307679 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature