抗GABAB受体自身免疫通过突触前病理导致认知衰退
Anti-GABAB receptor autoimmunity causes cognitive decline by presynaptic pathology
GABAB 受体通过突触前和突触后机制，是神经元传递与兴奋性的核心调控者。其功能障碍会导致严重的神经系统疾病，但其潜在的病理机制仍不清楚。在此，我们利用一种独特的中枢神经系统自身免疫性疾病，患者体内产生针对 GABAB 受体的特异性自身抗体，导致伴有严重记忆功能障碍和癫痫的自身免疫性脑炎。我们证明，人自身抗体靶向 GABAB 受体 B1a 亚基和 B2 亚基的 sushi 结构域，并干扰突触前信号传导。这种特定的突触前病理源于对 B1a 亚基的独占性功能拮抗，破坏短期和长期突触可塑性，在体内异常放大海马网络振荡及其耦合，并最终损害记忆巩固。我们的结果表明，仅自身免疫性突触前病理机制就足以干扰记忆加工，从而在分子水平的 GABAB 受体紊乱、突触病理、环路功能障碍与痴呆之间确立了因果联系，且区别于经典的神经退行性过程。
把自身免疫抗体当作分子工具，分离出GABAB受体突触前信号与记忆巩固之间的因果链条。
The GABAB receptor is a central regulator of neuronal transmission and excitability by pre- and postsynaptic mechanisms. Its dysfunction causes severe neurological disease, but the underlying pathomechanisms remain elusive. Here, we exploit a distinct CNS autoimmune disorder in which patients develop specific autoantibodies against GABAB receptors causing autoimmune encephalitis with severe memory dysfunction and epilepsy. We demonstrate that human autoantibodies target the sushi-domains of the GABAB receptor B1a subunit and the B2 subunit and interfere with presynaptic signaling. This specific presynaptic pathology results from exclusive functional antagonism of the B1a subunit and disrupts short- and long-term synaptic plasticity, abnormally amplifies hippocampal network oscillations and coupling in vivo, and ultimately impairs memory consolidation. Our results demonstrate that autoimmune presynaptic pathomechanisms alone are sufficient to interfere with memory processing, thus defining a causal link between molecular GABAB receptor disturbance, synaptic pathology, circuit dysfunction, and dementia distinct from classical neurodegenerative processes.
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来源：bioRxiv · Neuroscience · biorxiv.org