Laboratory of Electrophysiology, Nencki Institute of Experimental Biology, PAS, Warsaw, Poland; Laboratory of Animal Models, Nencki Institute of Experimental Biology PAS, Warsaw, Poland; Laboratory of Neurobiology, BRAINCITY, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Street, 02-093 Warsaw, Poland.
Laboratory of Animal Models, Nencki Institute of Experimental Biology PAS, Warsaw, Poland; Laboratory of Neurobiology, BRAINCITY, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Street, 02-093 Warsaw, Poland; Research and Development Centre, Celon Pharma SA, Kazun Nowy, Poland.
Neurosci Lett. 2022 Jul 27;784:136744. doi: 10.1016/j.neulet.2022.136744. Epub 2022 Jun 16.
Synaptic dysfunction is the prominent feature of many neuropsychiatric and neurological diseases, in which glycogen synthase kinase 3β (GSK-3β) has been shown to play a role. Overexpression of constitutively active form of GSK-3β (GSK-3β[S9A]) in mice recapitulates the cognitive and structural brain deficits characteristic for manic phase of bipolar disorder (BD). Yet, the mechanisms underlying GSK-3β-induced synaptic dysfunction have not been fully elucidated. The aim of the present study was to dissect the effect of GSK-3β overactivity on synaptic function in adolescent (3-week-old) mice. We found that overactivity of GSK-3β in adolescent transgenic mice leads to an alteration in dendritic spines morphology of granule cells in dentate gyrus (DG) without changes in overall spine density. There was an increase in the number of thin, presumably immature dendritic spines in GSK-3β[S9A] mice. Subsequent electrophysiological analysis showed changes in excitatory synaptic transmission manifested by an increase of inter-event intervals of miniature excitatory postsynaptic currents (mEPSCs) in DG granule cells and an increase in the number of silent (unfunctional) synapses at the perforant path-DG pathway in GSK-3β[S9A] mice. Altogether, our data indicate that GSK-3β overactivity leads to synaptic deficits in adolescent, GSK-3β[S9A] mice. These data might provide potential mechanisms underlying GSK-3β-induced synaptic dysfunction in psychiatric disorders.
突触功能障碍是许多神经精神和神经疾病的突出特征，其中糖原合酶激酶 3β（GSK-3β）已被证明起作用。在小鼠中过表达组成型激活形式的 GSK-3β（GSK-3β[S9A]）可重现双相情感障碍（BD）躁狂相的认知和结构脑缺陷。然而，GSK-3β 诱导的突触功能障碍的机制尚未完全阐明。本研究的目的是剖析 GSK-3β 过度活跃对青少年（3 周龄）小鼠突触功能的影响。我们发现，青少年转基因小鼠中 GSK-3β 的过度活跃导致齿状回（DG）颗粒细胞树突棘形态的改变，而总体棘密度没有变化。GSK-3β[S9A]小鼠中存在更多的薄的、推测为不成熟的树突棘。随后的电生理分析显示兴奋性突触传递发生变化，表现为 DG 颗粒细胞中微小兴奋性突触后电流（mEPSC）的事件间间隔增加，以及 GSK-3β[S9A]小鼠中穿通路径-DG 通路中的沉默（无功能）突触数量增加。总之，我们的数据表明 GSK-3β 过度活跃导致青少年 GSK-3β[S9A]小鼠的突触缺陷。这些数据可能为精神疾病中 GSK-3β 诱导的突触功能障碍提供潜在的机制。
