| First Author | Goodfellow NM | Year | 2014 |
| Journal | J Neurosci | Volume | 34 |
| Issue | 17 | Pages | 6107-11 |
| PubMed ID | 24760870 | Mgi Jnum | J:210608 |
| Mgi Id | MGI:5571522 | Doi | 10.1523/JNEUROSCI.3762-13.2014 |
| Citation | Goodfellow NM, et al. (2014) Mice with compromised 5-HTT function lack phosphotyrosine-mediated inhibitory control over prefrontal 5-HT responses. J Neurosci 34(17):6107-11 |
| abstractText | The activity of the prefrontal cortex is essential for normal emotional processing and is strongly modulated by serotonin (5-HT). Yet, little is known about the regulatory mechanisms that control the activity of the prefrontal 5-HT receptors. Here, we found and characterized a deregulation of prefrontal 5-HT receptor electrophysiological signaling in mouse models of disrupted serotonin transporter (5-HTT) function, a risk factor for emotional and cognitive disturbances. We identified a novel tyrosine kinase-dependent mechanism that regulates 5-HT-mediated inhibition of prefrontal pyramidal neurons. We report that mice with compromised 5-HTT, resulting from either genetic deletion or brief treatment with selective serotonin reuptake inhibitors during development, have amplified 5-HT1A receptor-mediated currents in adulthood. These greater inhibitory effects of 5-HT are accompanied by enhanced downstream coupling to Kir3 channels. Notably, in normal wild-type mice, we found that these larger 5-HT1A responses can be mimicked through inhibition of Src family tyrosine kinases. By comparison, in our 5-HTT mouse models, the larger 5-HT1A responses were rapidly reduced through inhibition of tyrosine phosphatases. Our findings implicate tyrosine phosphorylation in regulating the electrophysiological effects of prefrontal 5-HT1A receptors with implications for neuropsychiatric diseases associated with emotional dysfunction, such as anxiety and depressive disorders. |
