Syngap1 突变体认知能力下降是由于发育中前脑兴奋性神经元的孤立损伤引起的。
Reduced cognition in Syngap1 mutants is caused by isolated damage within developing forebrain excitatory neurons.
机构信息
Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA 92797, USA.
出版信息
Neuron. 2014 Jun 18;82(6):1317-33. doi: 10.1016/j.neuron.2014.05.015.
Syngap1 haploinsufficiency is a common cause of sporadic intellectual disability. Syngap1 mutations disrupt developing pyramidal neurons, although it remains unclear if this process contributes to cognitive abnormalities. Here, we found that haploinsufficiency restricted to forebrain glutamatergic neurons was sufficient to disrupt cognition and removing mutations from this population prevented cognitive abnormalities. In contrast, manipulating Syngap1 function in GABAergic neurons had no effect on cognition, excitability, or neurotransmission, highlighting the specificity of Syngap1 mutations within forebrain excitatory neurons. Interestingly, cognitive abnormalities were reliably predicted by the emergence of enhanced excitatory synaptic function in mature superficial cortical pyramidal cells, which was a neurophysiological disruption caused by Syngap1 dysfunction in developing, but not adult, forebrain neurons. We conclude that reduced cognition in Syngap1 mutants is caused by isolated damage to developing forebrain glutamatergic neurons. This damage triggers secondary disruptions to synaptic homeostasis in mature cortical pyramidal cells, which perpetuates brain dysfunction into adulthood.
Syngap1 杂合性不足是散发性智力障碍的常见原因。Syngap1 突变会破坏正在发育的锥体神经元，尽管尚不清楚这一过程是否导致认知异常。在这里，我们发现仅局限于前脑谷氨酸能神经元的杂合性不足足以破坏认知，并且从该群体中去除突变可防止认知异常。相比之下，在前脑兴奋性神经元中操纵 Syngap1 功能对认知、兴奋性或神经递质传递没有影响，突出了 Syngap1 突变在前脑兴奋性神经元中的特异性。有趣的是，增强成熟的浅层皮质锥体神经元中兴奋性突触功能的出现可靠地预测了认知异常，这是由发育中的而非成年的前脑神经元中 Syngap1 功能障碍引起的神经生理破坏。我们得出结论，Syngap1 突变体的认知能力降低是由发育中的前脑谷氨酸能神经元的孤立损伤引起的。这种损伤触发成熟皮质锥体神经元中突触稳态的继发性破坏，从而使大脑功能障碍持续到成年期。
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