UNICAEN, INSERM, COMETE, CYCERON, CHU Caen, Normandie Université, 14000 Caen, France.
Inserm U1216, CEA, Grenoble Institut Neurosciences, Université Grenoble Alpes, 38000 Grenoble, France.
Int J Mol Sci. 2021 Mar 5;22(5):2644. doi: 10.3390/ijms22052644.
For a better translation from treatment designs of schizophrenia to clinical efficiency, there is a crucial need to refine preclinical animal models. In order to consider the multifactorial nature of the disorder, a new mouse model associating three factors (genetic susceptibility-partial deletion of the gene, early-life stress-maternal separation, and pharmacological treatment-chronic Δ-9-tetrahydrocannabinol during adolescence) has recently been described. While this model depicts a schizophrenia-like phenotype, the neurobiological correlates remain unknown. Synaptic transmission and functional plasticity of the CA1 hippocampal region of male and female 3-hit mice were therefore investigated using electrophysiological recordings on the hippocampus slice. While basal excitatory transmission remained unaffected, NMDA receptor (NMDAr)-mediated long-term potentiation (LTP) triggered by theta-burst (TBS) but not by high-frequency (HFS) stimulation was impaired in 3-hit mice. Isolated NMDAr activation was not affected or even increased in female 3-hit mice, revealing a sexual dimorphism. Considering that the regulation of LTP is more prone to inhibitory tone if triggered by TBS than by HFS, the weaker potentiation in 3-hit mice suggests a deficiency of intrinsic GABA regulatory mechanisms. Indeed, NMDAr activation was increased by GABA receptor blockade in wild-type but not in 3-hit mice. This electrophysiological study highlights dysregulations of functional properties and plasticity in hippocampal networks of 3-hit mice, one of the mechanisms suspected to contribute to the pathophysiology of schizophrenia. It also shows differences between males and females, supporting the sexual dimorphism observed in the disorder. Combined with the previously reported study, the present data reinforce the face validity of the 3-hit model that will help to consider new therapeutic strategies for psychosis.
为了使精神分裂症的治疗设计更好地转化为临床疗效，迫切需要改进临床前动物模型。为了考虑到该疾病的多因素性质，最近描述了一种新的关联三种因素（遗传易感性-基因部分缺失、早期生活应激-母婴分离和药物治疗-青春期慢性Δ-9-四氢大麻酚）的小鼠模型。虽然该模型描述了一种类似精神分裂症的表型，但神经生物学相关性仍不清楚。因此，使用海马切片上的电生理记录研究了雄性和雌性 3 击小鼠 CA1 海马区的突触传递和功能可塑性。虽然基础兴奋性传递不受影响，但 TBS 而非 HFS 刺激引发的 NMDA 受体（NMDAr）介导的长时程增强（LTP）在 3 击小鼠中受损。单独激活 NMDAr 在雌性 3 击小鼠中不受影响甚至增加，显示出性别二态性。考虑到如果由 TBS 而不是 HFS 触发，LTP 的调节更容易受到抑制性音调的影响，因此 3 击小鼠中的较弱增强表明内在 GABA 调节机制的缺陷。事实上，GABA 受体阻断剂增加了野生型小鼠而非 3 击小鼠中 NMDAr 的激活。这项电生理研究强调了 3 击小鼠海马网络功能特性和可塑性的失调，这是导致精神分裂症病理生理学的机制之一。它还显示了男性和女性之间的差异，支持了该疾病中观察到的性别二态性。结合之前的研究报告，本数据加强了 3 击模型的表面有效性，该模型将有助于考虑精神分裂症的新治疗策略。
