Polepalli Jai S, Wu Hemmings, Goswami Debanjan, Halpern Casey H, Südhof Thomas C, Malenka Robert C
Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California, USA.
Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA.
Nat Neurosci. 2017 Feb;20(2):219-229. doi: 10.1038/nn.4471. Epub 2017 Jan 9.
Hippocampal network activity is generated by a complex interplay between excitatory pyramidal cells and inhibitory interneurons. Although much is known about the molecular properties of excitatory synapses on pyramidal cells, comparatively little is known about excitatory synapses on interneurons. Here we show that conditional deletion of the postsynaptic cell adhesion molecule neuroligin-3 in parvalbumin interneurons causes a decrease in NMDA-receptor-mediated postsynaptic currents and an increase in presynaptic glutamate release probability by selectively impairing the inhibition of glutamate release by presynaptic Group III metabotropic glutamate receptors. As a result, the neuroligin-3 deletion altered network activity by reducing gamma oscillations and sharp wave ripples, changes associated with a decrease in extinction of contextual fear memories. These results demonstrate that neuroligin-3 specifies the properties of excitatory synapses on parvalbumin-containing interneurons by a retrograde trans-synaptic mechanism and suggest a molecular pathway whereby neuroligin-3 mutations contribute to neuropsychiatric disorders.
海马体网络活动是由兴奋性锥体细胞和抑制性中间神经元之间复杂的相互作用产生的。虽然我们对锥体细胞上兴奋性突触的分子特性了解很多，但对中间神经元上的兴奋性突触却知之甚少。在这里，我们表明，在小白蛋白中间神经元中条件性删除突触后细胞粘附分子神经连接蛋白-3会导致NMDA受体介导的突触后电流减少，并且通过选择性损害突触前III型代谢型谷氨酸受体对谷氨酸释放的抑制作用，使突触前谷氨酸释放概率增加。结果，神经连接蛋白-3的缺失通过减少伽马振荡和尖波涟漪改变了网络活动，这些变化与情境恐惧记忆消退减少有关。这些结果表明，神经连接蛋白-3通过逆行跨突触机制确定了含小白蛋白中间神经元上兴奋性突触的特性，并提示了一条神经连接蛋白-3突变导致神经精神疾病的分子途径。
