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.
Highlights
Synaptic inhibition plays a fundamental role in the information processing of neural circuits
Because the percentage of GABAergic neurons in the striatum is relatively much higher than the ones in the cortex and the hippocampus, the expression of phospholipase Cγ1 (PLCγ1) appeared significantly decreased only in the striatum compared with the cortex and the hippocampus (Fig. S1a,b)
The gene expression of GAD 65, a GABA-synthesizing enzyme localized at axon terminals, involves CREB-dependent Brain-derived neurotrophic factor (BDNF)/ TrkB signaling in cortical neurons[24]
Summary
Synaptic inhibition plays a fundamental role in the information processing of neural circuits. Neuron-specific TrkB conditional knockout mice show reduced seizure susceptibility in kindling epilepsy model and the disrupted interaction between TrkB and PLCγ1 prevents the generation of seizure[12,13,14] Despite these findings, there remains a good deal of uncertainty about the specific role of PLCγ1 in the etiology of epileptogenesis. GABAergic neuron-specific PLCγ1 conditional knockout mice, Plcg1F/F; Dlx5/6-Cre, exhibit the handling-induced recurrent seizures and epileptic EEG patterns when they are at least 6 months old. This occurrence of seizure is accompanied by other behavioral alterations including hypoactivity, reduced anxiety, and impaired fear memory. Our findings suggest that PLCγ1 may be one of principal molecular determinants modulating hippocampal circuit by maintaining the proper level of synaptic inhibition via GABAergic interneurons
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
