Division of Physiology, Medical University Innsbruck, 6020 Innsbruck, Austria, and.
Institute of Anatomy and Molecular Neurobiology, Westfälische Wilhelms-University, 48149 Münster, Germany.
J Neurosci. 2019 Apr 3;39(14):2581-2605. doi: 10.1523/JNEUROSCI.2234-18.2019. Epub 2019 Jan 25.
Presynaptic αδ subunits of voltage-gated calcium channels regulate channel abundance and are involved in glutamatergic synapse formation. However, little is known about the specific functions of the individual αδ isoforms and their role in GABAergic synapses. Using primary neuronal cultures of embryonic mice of both sexes, we here report that presynaptic overexpression of αδ-2 in GABAergic synapses strongly increases clustering of postsynaptic GABARs. Strikingly, presynaptic αδ-2 exerts the same effect in glutamatergic synapses, leading to a mismatched localization of GABARs. This mismatching is caused by an aberrant wiring of glutamatergic presynaptic boutons with GABAergic postsynaptic positions. The trans-synaptic effect of αδ-2 is independent of the prototypical cell-adhesion molecules α-neurexins (α-Nrxns); however, α-Nrxns together with αδ-2 can modulate postsynaptic GABAR abundance. Finally, exclusion of the alternatively spliced exon 23 of αδ-2 is essential for the trans-synaptic mechanism. The novel function of αδ-2 identified here may explain how abnormal αδ subunit expression can cause excitatory-inhibitory imbalance often associated with neuropsychiatric disorders. Voltage-gated calcium channels regulate important neuronal functions such as synaptic transmission. αδ subunits modulate calcium channels and are emerging as regulators of brain connectivity. However, little is known about how individual αδ subunits contribute to synapse specificity. Here, we show that presynaptic expression of a single αδ variant can modulate synaptic connectivity and the localization of inhibitory postsynaptic receptors. Our findings provide basic insights into the development of specific synaptic connections between nerve cells and contribute to our understanding of normal nerve cell functions. Furthermore, the identified mechanism may explain how an altered expression of calcium channel subunits can result in aberrant neuronal wiring often associated with neuropsychiatric disorders such as autism or schizophrenia.
电压门控钙通道的突触前 αδ 亚基调节通道丰度，并参与谷氨酸能突触形成。然而，对于个别 αδ 同工型的特定功能及其在 GABA 能突触中的作用知之甚少。使用来自雌雄胚胎小鼠的原代神经元培养物，我们在此报告在 GABA 能突触中突触前过表达 αδ-2 强烈增加了突触后 GABAR 的聚集。引人注目的是，αδ-2 在谷氨酸能突触中发挥相同的作用，导致 GABAR 的定位不匹配。这种不匹配是由谷氨酸能突触前末梢与 GABA 能突触后位置的异常连接引起的。αδ-2 的跨突触效应独立于典型的细胞粘附分子 α-neurexins（α-Nrxns）；然而，α-Nrxns 与 αδ-2 一起可以调节突触后 GABAR 的丰度。最后，αδ-2 的选择性剪接外显子 23 的排除对于跨突触机制是必需的。这里鉴定的 αδ-2 的新功能可以解释异常的 αδ 亚基表达如何导致与神经精神障碍相关的兴奋性-抑制性失衡。电压门控钙通道调节突触传递等重要神经元功能。αδ 亚基调节钙通道，并作为脑连接的调节剂出现。然而，对于个别 αδ 亚基如何有助于突触特异性知之甚少。在这里，我们表明单个 αδ 变体的突触前表达可以调节突触连接和抑制性突触后受体的定位。我们的研究结果为神经细胞之间特定突触连接的发展提供了基本的见解，并有助于我们理解正常神经细胞功能。此外，所鉴定的机制可以解释钙通道亚基的表达改变如何导致与神经精神障碍（如自闭症或精神分裂症）相关的异常神经元连接。
