Human CLOCK enhances cognitive flexibility by altering cortical excitatory neuron function
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ABSTRACT:
PROVIDER: PRJNA932429 | ENA |
REPOSITORIES: ENA
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Project description:A BAC containing human CLOCK gene with flanking regulatory region was transferred to mice. The humazied (HU) mice outperformed wildtype (WT) in a reversal learning task, and hence suggested enhanced cognitive flexibility in HU mice. IHC of frontal cortex suggested that the enhanced cognitive flexibility in HU mice might result from the increased neuronal density, dendritic arborization, and spine density. In order to determine the molecular mechanism, we conducted single-nuclei RNA-seq on frontal cortex from postnatal 7 day (P7) and P56 mice. In the excitatory neuron, genes that upregulated in HU mice were enriched for dendritic growth (e.g. Tenm2 and Flrt2), spine formation (e.g. Cntn5 and Sorcs2), and energy metabolism (e.g. Suclg1 and Cox8a).
2025-04-18 | GSE224759 | GEO
Project description:Synapse development and neuronal activity represent fundamental processes for the establishment of cognitive function. Structural organization as well as signalling pathways from receptor stimulation to gene expression regulation are mediated by synaptic activity and misregulated in neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID). Deleterious mutations in the PTCHD1 (Patched domain containing 1) gene have been described in male patients with X-linked ID and/or ASD. The structure of PTCHD1 protein is similar to the Patched (PTCH1) receptor; however, the cellular mechanisms and pathways associated with PTCHD1 in the developing brain are poorly determined. Here we show that PTCHD1 displays a C-terminal PDZ-binding motif that binds to the postsynaptic proteins PSD95 and SAP102. We also report that PTCHD1 is unable to rescue the canonical sonic hedgehog (SHH) pathway in cells depleted of PTCH1, suggesting that both proteins are involved in distinct cellular signalling pathways. We find that Ptchd1 deficiency in male mice (Ptchd1-/y) induces global changes in synaptic gene expression, affects the expression of the immediate-early expression genes Egr1 and Npas4 and finally impairs excitatory synaptic structure and neuronal excitatory activity in the hippocampus, leading to cognitive dysfunction, motor disabilities and hyperactivity. Thus our results support that PTCHD1 deficiency induces a neurodevelopmental disorder causing excitatory synaptic dysfunction.
2017-04-14 | GSE80312 | GEO
Project description:Maternal immune activation impairs cognitive flexibility and alters transcription in frontal cortex
| PRJNA565729 | ENA
Project description:Rattus norvegicus Clock, clock circadian regulator [Source:RGD Symbol;Acc:620271], is differentially expressed in 35 experiment(s);
| ENSRNOG00000002175 | ExpressionAtlas
Project description:Rattus norvegicus Clock, clock circadian regulator [Source:RGD Symbol;Acc:620271], is expressed in 6 baseline experiment(s);
| ENSRNOG00000002175 | ExpressionAtlas
Project description:Monodelphis domestica CLOCK, clock circadian regulator [Source:NCBI gene;Acc:100017022], is expressed in 2 baseline experiment(s);
| ENSMODG00000020678 | ExpressionAtlas
Project description:Sus scrofa CLOCK, clock circadian regulator [Source:VGNC Symbol;Acc:VGNC:86774], is expressed in 2 baseline experiment(s);
| ENSSSCG00000008909 | ExpressionAtlas
Project description:Macaca mulatta CLOCK, clock circadian regulator [Source:VGNC Symbol;Acc:VGNC:71262], is expressed in 2 baseline experiment(s);
| ENSMMUG00000001919 | ExpressionAtlas
Project description:Homo sapiens CLOCK, clock circadian regulator [Source:HGNC Symbol;Acc:HGNC:2082], is differentially expressed in 149 experiment(s);
| ENSG00000134852 | ExpressionAtlas
Project description:Oryctolagus cuniculus CLOCK, clock circadian regulator [Source:HGNC Symbol;Acc:HGNC:2082], is expressed in 1 baseline experiment(s);
| ENSOCUG00000022350 | ExpressionAtlas