Beclin1 Deficiency Suppresses Epileptic Seizures

Abstract

Epilepsy is a common disease of the nervous system. Autophagy is a degradation process involved in epilepsy, and in turn, seizures can activate autophagy. Beclin1 plays a critical role in autophagy and participates in numerous physiological and pathological processes. However, the mechanism underlying the effect of Beclin1 on epilepsy remains unclear. In this study, we detected increased expression of Beclin1 in brain tissues from patients with temporal lobe epilepsy (TLE). Heterozygous disruption of beclin1 decreased susceptibility to epilepsy and suppressed seizure activity in two mouse epilepsy models. We further illustrated for the first time that heterozygous disruption of beclin1 suppresses excitatory synaptic transmission, which may be caused by a decreased dendritic spine density. These findings suggest for the first time that the regulation of Beclin1 may serve as a strategy for antiepileptic therapy. In addition, Beclin1 participates in synaptic transmission, and the development of dendritic spines may be a biological function of Beclin1 independent of its role in autophagy.

Increased regional activity of a pro-autophagy pathway in schizophrenia as a contributor to sex differences in the disease pathology

“…Notably, non-conditional beclin-1 heterozygous knockout mice exhibit a reduction in baseline in vivo dendritic spine density in cortical pyramidal neurons as well as a reduced spine density in cultured hippocampal neurons that is accompanied by a reduction in PSD-95 puncta. 17 Further, although short hairpin RNA (shRNA)-mediated knockdown of beclin-1 did not reduce baseline spine density in hippocampal neurons in vitro or in vivo , it did fully block the effect of chemical long term potentiation (LTP) on de novo spine formation in cultured neurons and on learning/memory-mediated spine formation in vivo . 18 Whereas beclin-1 knockdown has spine-destabilizing effects, our findings indicate that enhancing beclin-1 activity has spine-facilitating effects.…”

“…Notably, rather than causing the expected increase in dendritic spine stability, the knockdown of proteins that directly facilitate autophagy can in many cases decrease the density of dendritic spines in vitro and in vivo . 16 , 17 , 18 This highlights the need to examine the synaptic consequences of proteins involved in the regulation of autophagy on an individual basis. Consistent with its effects in controlling synaptic stability, maintaining neuronal autophagy within a normal physiological range is critical for proper cognition.…”