| First Author | Zhou M | Year | 2020 |
| Journal | Mol Psychiatry | Volume | 25 |
| Issue | 12 | Pages | 3322-3336 |
| PubMed ID | 31363163 | Mgi Jnum | J:319513 |
| Mgi Id | MGI:6864396 | Doi | 10.1038/s41380-018-0233-z |
| Citation | Zhou M, et al. (2020) CK1delta over-expressing mice display ADHD-like behaviors, frontostriatal neuronal abnormalities and altered expressions of ADHD-candidate genes. Mol Psychiatry 25(12):3322-3336 |
| abstractText | The cognitive mechanisms underlying attention-deficit hyperactivity disorder (ADHD), a highly heritable disorder with an array of candidate genes and unclear genetic architecture, remain poorly understood. We previously demonstrated that mice overexpressing CK1delta (CK1delta OE) in the forebrain show hyperactivity and ADHD-like pharmacological responses to D-amphetamine. Here, we demonstrate that CK1delta OE mice exhibit impaired visual attention and a lack of D-amphetamine-induced place preference, indicating a disruption of the dopamine-dependent reward pathway. We also demonstrate the presence of abnormalities in the frontostriatal circuitry, differences in synaptic ultra-structures by electron microscopy, as well as electrophysiological perturbations of both glutamatergic and GABAergic transmission, as observed by altered frequency and amplitude of mEPSCs and mIPSCs. Furthermore, gene expression profiling by next-generation sequencing alone, or in combination with bacTRAP technology to study specifically Drd1a versus Drd2 medium spiny neurons, revealed that developmental CK1delta OE alters transcriptional homeostasis in the striatum, including specific alterations in Drd1a versus Drd2 neurons. These results led us to perform a fine molecular characterization of targeted gene networks and pathway analysis. Importantly, a large fraction of 92 genes identified by GWAS studies as associated with ADHD in humans are significantly altered in our mouse model. The multiple abnormalities described here might be responsible for synaptic alterations and lead to complex behavioral abnormalities. Collectively, CK1delta OE mice share characteristics typically associated with ADHD and should represent a valuable model to investigate the disease in vivo. |
