Deletion of PLC??1 in GABAergic neurons increases seizure susceptibility in aged mice

Synaptic inhibition plays a fundamental role in the information processing of neural circuits. It sculpts excitatory signals and prevents hyperexcitability of neurons. Owing to these essential functions, dysregulated synaptic inhibition causes a plethora of neurological disorders, including epilepsy, autism, and schizophrenia. Among these disorders, epilepsy is associated with abnormal hyperexcitability of neurons caused by the deficits of GABAergic neuron or decreased GABAergic inhibition at synapses. Although many antiepileptic drugs are intended to improve GABA-mediated inhibition, the molecular mechanisms of synaptic inhibition regulated by GABAergic neurons are not fully understood. Increasing evidence indicates that phospholipase C??1 (PLC??1) is involved in the generation of seizure, while the causal relationship between PLC??1 and seizure has not been firmly established yet. Here, we show that genetic deletion of PLC??1 in GABAergic neurons leads to handling-induced seizure in aged mice. In addition, aged Plcg1F/F; Dlx5/6-Cre mice exhibit other behavioral alterations, including hypoactivity, reduced anxiety, and fear memory deficit. Notably, inhibitory synaptic transmission as well as the number of inhibitory synapses are decreased in the subregions of hippocampus. These findings suggest that PLC??1 may be a key determinant of maintaining both inhibitory synapses and synaptic transmission, potentially contributing to the regulation of E/I balance in the hippocampus

Physical and Functional Interaction between 5-HT6 Receptor and Nova-1

5-HT6 receptor (5-HT6R) is implicated in cognitive dysfunction, mood disorder, psychosis, and eating disorders. However, despite its significant role in regulating the brain functions, regulation of 5-HT6R at the molecular level is poorly understood. Here, using yeast two-hybrid assay, we found that human 5-HT6R directly binds to neuro-oncological ventral antigen 1 (Nova-1), a brain-enriched splicing regulator. The interaction between 5-HT6R and Nova-1 was confirmed using GST pull-down and co-immunoprecipitation assays in cell lines and rat brain. The splicing activity of Nova-1 was decreased upon overexpression of 5-HT6R, which was examined by detecting the spliced intermediates of gonadotropin-releasing hormone (GnRH), a known pre-mRNA target of Nova-1, using RT-PCR. In addition, overexpression of 5-HT6R induced the translocation of Nova-1 from the nucleus to cytoplasm, resulting in the reduced splicing activity of Nova-1. In contrast, overexpression of Nova-1 reduced the activity and the total protein levels of 5-HT6R. Taken together, these results indicate that when the expression levels of 5-HT6R or Nova-1 protein are not properly regulated, it may also deteriorate the function of the other. Copyright © Experimental Neurobiology 2019.1

Deletion of PLC??1 in GABAergic Neurons Leads to Spontaneous Seizure in Mice

Excitation/inhibition (E/I) balance plays a fundamental role in information processing of neural circuits. It coordinates various neural functions and dysregulated E/I balance causes multiple neurological disorders. Among them, epilepsy is associated with hyperexcitability of neurons caused by the deficits of GABAergic neuron or decreased GABAergic inhibition at synapses. Although many antiepileptic drugs are intended to improve GABAmediated inhibition via GABAergic interneurons, molecular mechanisms of E/I balance regulated by GABAergic neurons are not fully understood. Increasing evidence indicates that phospholipase C ??1 (PLC??1) is involved in the generation of seizure, while the causal relationship between PLC??1 and seizure has not been firmly established. Here, we show that genetic deletion of PLC??1 in GABAergic neurons leads to spontaneous seizure. Plcg1F/F;Dlx5/6-Cre mice also exhibits other behavioral alterations, including hypoactivity, reduced anxiety, and fear memory deficit. Notably, inhibitory synaptic transmission as well as the number of inhibitory synapses are decreased in hippocampus. These findings suggest that PLC??1 may be a key determinant of maintaining both inhibitory synapses and synaptic transmission, potentially contributing to the regulation of E/I balance in hippocampus