Deletion of PLCγ1 in GABAergic neurons increases seizure susceptibility in aged mice

Abstract

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 Cγ1 (PLCγ1) is involved in the generation of seizure, while the causal relationship between PLCγ1 and seizure has not been firmly established yet. Here, we show that genetic deletion of PLCγ1 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 PLCγ1 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.

Effects of maternal immune activation in porcine transcript isoforms of neuropeptide and receptor genes

“…The detected effect of MIA on PLCG1 is consistent with reports that PLCG1 participates in the interactome of schizophrenia [50]. Genetic deletions of PLCG1 in mice exhibited behavioral alterations, including hypoactivity and reduced anxiety [51]. The NPY transcript isoform profile detected in this study is also consistent with reports that the expression of NPY (a member of the neuroactive ligandreceptor interaction pathway) was altered in the dorsolateral prefrontal cortex of individuals with schizophrenia [52].…”

Phospholipase C families: Common themes and versatility in physiology and pathology

“…The above studies have focused on the role of PLCγ1 for epileptogenesis in excitatory neurons. In a study where PLCγ1 was specifically deleted from inhibitory GABAergic neurons genetically, mice developed handling-induced seizures in aged mice [272]. In…”

The γ-Protocadherins Regulate the Survival of GABAergic Interneurons during Developmental Cell Death

“…(1) stiffness and rigid posturing; (2) head nodding and tilting; (3) partial forelimb clonus; (4) whole body seizures; (5) motor convulsions, including falling, forelimb clonus and jumping (Racine, 1972;Kim et al, 2019).…”

“…Cortical EEG recordings were combined with video to monitor wild-type sibling and Pcdhg GcKO mutant mice (three months of age, N = 4 animals per genotype). Periods of extended immobility were identified and assessed for behavioral seizures using a modified Racine scale (Racine, 1972;Kim et al, 2019). During these periods (immobile 59 63% SEM of recorded time; N = 4 animals), Pcdhg GcKO mutant exhibited seizure symptoms and convulsive behaviors, including stiff posturing (scale 1), nodding and forelimb clonus (scale 2, 3), and in a few severe instances, continuous whole-body seizures (scale 4; Fig.…”