| First Author | Khlghatyan J | Year | 2020 |
| Journal | CRISPR J | Volume | 3 |
| Issue | 3 | Pages | 198-210 |
| PubMed ID | 32584144 | Mgi Jnum | J:292101 |
| Mgi Id | MGI:6445468 | Doi | 10.1089/crispr.2019.0075 |
| Citation | Khlghatyan J, et al. (2020) CRISPR-Cas9-Mediated Intersectional Knockout of Glycogen Synthase Kinase 3beta in D2 Receptor-Expressing Medial Prefrontal Cortex Neurons Reveals Contributions to Emotional Regulation. CRISPR J 3(3):198-210 |
| abstractText | Glycogen synthase kinase 3beta (GSK3beta) activity is regulated by dopamine D2 receptor signaling and can be inhibited by psychoactive drugs in a D2 receptor-dependent manner. However, GSK3beta 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 GSK3beta 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 GSK3beta in D2-expressing neurons of the adult medial prefrontal cortex (mPFC). Isolation and analysis of ribosome-associated RNA specifically from mPFC D2 neurons lacking GSK3beta demonstrated large-scale translatome alterations. Deletion of GSK3beta 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 GSK3beta expressed in mPFC D2 neurons in the regulation of behavioral dimensions related to mood and emotions. This advances our understanding of GSK3beta action at a brain circuit level and can potentially lead to the development of circuit selective therapeutics. |
