Biomedical Research Center, Institute of Experimental Endocrinology, The Slovak Academy of Sciences, Dubravska cesta 9, 845 05, Bratislava, Slovakia.
Faculty of Medicine, Institute of Molecular Biomedicine, Comenius University in Bratislava, Bratislava, Slovakia.
Neurochem Res. 2021 Dec;46(12):3342-3355. doi: 10.1007/s11064-021-03435-6. Epub 2021 Aug 28.
Alterations in the balance between excitation and inhibition, especially in the brain's critical developmental periods, are considered an integral part of the pathophysiology of autism. However, the precise mechanisms have not yet been established. SH3 and multiple Ankyrin repeat domains 3 (Shank3) deficient mice represent a well-established transgenic model of a neurodevelopmental disorder with autistic symptomatology. In this study, we characterize the consequences of Shank3 deficiency according to (1) expression of specific markers of different neuronal populations in pups and adult mice and (2) social behaviour and anxiety in adult mice. Our research found enhanced expression of serotonin transporter and choline acetyltransferase in the hippocampus and hypothalamus in Shank3-deficient pups. We demonstrated marked brain region differences in expression of excitatory glutamatergic markers in pups and adult Shank3 deficient mice. We also observed reduced expression of inhibitory GABAergic markers and GABA receptor subunits in several brain areas in both pups and adult Shank3 deficient mice. Further analysis of dopaminergic brain areas (nucleus accumbens, ventral tegmental area) revealed lower expression levels of GABAergic markers in adult Shank3 deficient mice. Adult Shank3 deficient mice exhibited excessive repetitive behaviour, a higher level of anxiety, and lower locomotor activity. Our data support the theory of an imbalance between excitatory and inhibitory neurotransmission in conditions of abnormal SHANK3 protein. We therefore suggest that autism-like conditions are accompanied by reduced expression of GABAergic markers in the brain during early development as well as in the adult age, which could be associated with long-lasting behavioural abnormalities.
兴奋与抑制之间的平衡改变，尤其是在大脑的关键发育期，被认为是自闭症病理生理学的一个组成部分。然而，确切的机制尚未确定。SH3 和多个锚蛋白重复结构域 3（Shank3）缺失小鼠是一种具有自闭症症状的神经发育障碍的成熟转基因模型。在这项研究中，我们根据（1）不同神经元群体在幼鼠和成年小鼠中的特定标志物表达和（2）成年小鼠的社会行为和焦虑来描述 Shank3 缺失的后果。我们的研究发现，Shank3 缺失幼鼠的海马体和下丘脑中的 5-羟色胺转运体和胆碱乙酰转移酶表达增强。我们在幼鼠和成年 Shank3 缺失小鼠中观察到兴奋性谷氨酸能标志物的表达在大脑区域存在明显差异。我们还观察到，在幼鼠和成年 Shank3 缺失小鼠的多个脑区中，抑制性 GABA 能标志物和 GABA 受体亚基的表达减少。对多巴胺能脑区（伏隔核、腹侧被盖区）的进一步分析显示，成年 Shank3 缺失小鼠中的 GABA 能标志物表达水平较低。成年 Shank3 缺失小鼠表现出过度重复行为、更高的焦虑水平和更低的运动活性。我们的数据支持兴奋性和抑制性神经递质传递不平衡的理论，这种不平衡存在于异常 SHANK3 蛋白的情况下。因此，我们认为，在早期发育和成年期，自闭症样条件伴随着大脑中 GABA 能标志物表达减少，这可能与长期的行为异常有关。
