Reduced expression of the psychiatric risk gene DLG2 (PSD93) impairs hippocampal synaptic integration and plasticity.
Reduced expression of the psychiatric risk gene DLG2 (PSD93) impairs hippocampal synaptic integration and plasticity.
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DOI：
10.1038/s41386-022-01277-6
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发表时间：
2022-06
影响因子：
7.6
通讯作者：
Mellor, Jack R.
中科院分区：
文献类型：
--
作者：
Griesius, Simonas;O'Donnell, Cian;Waldron, Sophie;Thomas, Kerrie L.;Dwyer, Dominic M.;Wilkinson, Lawrence S.;Hall, Jeremy;Robinson, Emma S. J.;Mellor, Jack R.
表明DLG 2基因功能丧失的拷贝数变异与精神分裂症、自闭症谱系障碍和智力残疾的风险显著增加相关。DLG 2编码突触后支架蛋白DLG 2（PSD 93），其与NMDA受体、钾通道和细胞骨架调节剂相互作用，但这些相互作用对突触可塑性的净影响（可能是与这些条件相关的认知障碍的基础）仍不清楚。在此，使用离体膜片钳电生理学、药理学和计算建模，在一种新的临床相关杂合Dlg 2 +/−大鼠模型中研究了海马CA 1区神经元兴奋性和突触功能。Dlg 2 +/−大鼠突触输入的超线性树突整合减少，导致联合长时程增强受损。这种损害不是由突触输入的变化引起的，因为NMDA受体介导的突触电流相反地增加，AMPA受体介导的电流不受影响。相反，在联合长时程增强的损害导致钾通道功能的增加，导致输入电阻的降低，从而减少了超线性树突状整合。通过阻断钾通道或用选择性别构激动剂77-LH-28-1激活毒蕈碱M1受体来增强树突兴奋性，降低了树突整合的阈值，77-LH-28-1挽救了Dlg 2 +/−大鼠的联合长时程增强损伤。这些发现证明了一种生物表型，可以通过临床使用的化合物类别（如毒蕈碱M1受体激动剂）逆转，因此是治疗干预的潜在靶点。
Copy number variants indicating loss of function in the DLG2 gene have been associated with markedly increased risk for schizophrenia, autism spectrum disorder, and intellectual disability. DLG2 encodes the postsynaptic scaffolding protein DLG2 (PSD93) that interacts with NMDA receptors, potassium channels, and cytoskeletal regulators but the net impact of these interactions on synaptic plasticity, likely underpinning cognitive impairments associated with these conditions, remains unclear. Here, hippocampal CA1 neuronal excitability and synaptic function were investigated in a novel clinically relevant heterozygous Dlg2+/− rat model using ex vivo patch-clamp electrophysiology, pharmacology, and computational modelling. Dlg2+/− rats had reduced supra-linear dendritic integration of synaptic inputs resulting in impaired associative long-term potentiation. This impairment was not caused by a change in synaptic input since NMDA receptor-mediated synaptic currents were, conversely, increased and AMPA receptor-mediated currents were unaffected. Instead, the impairment in associative long-term potentiation resulted from an increase in potassium channel function leading to a decrease in input resistance, which reduced supra-linear dendritic integration. Enhancement of dendritic excitability by blockade of potassium channels or activation of muscarinic M1 receptors with selective allosteric agonist 77-LH-28-1 reduced the threshold for dendritic integration and 77-LH-28-1 rescued the associative long-term potentiation impairment in the Dlg2+/− rats. These findings demonstrate a biological phenotype that can be reversed by compound classes used clinically, such as muscarinic M1 receptor agonists, and is therefore a potential target for therapeutic intervention.
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DOI：
10.1186/s13195-021-00816-5
发表时间：
2021-04-21
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Bakker C;Tasker T;Liptrot J;Hart EP;Klaassen ES;Doll RJ;Brown GA;Brown A;Congreve M;Weir M;Marshall FH;Cross DM;Groeneveld GJ;Nathan PJ
通讯作者：
Nathan PJ
影响因子：
16.2
作者：
Elias, Guillermo M.;Funke, Lars;Nicoll, Roger A.
通讯作者：
Nicoll, Roger A.
影响因子：
4.7
作者：
Dakoji, S;Tomita, S;Bredt, DS
通讯作者：
Bredt, DS
DOI：
10.1093/cercor/bhv227
发表时间：
2016-01
期刊：
Cerebral cortex (New York, N.Y. : 1991)
影响因子：
--
作者：
Dennis SH;Pasqui F;Colvin EM;Sanger H;Mogg AJ;Felder CC;Broad LM;Fitzjohn SM;Isaac JT;Mellor JR
通讯作者：
Mellor JR
影响因子：
2.2
作者：
Egger, Gerald;Roetzer, Katharina M.;Vincent, John B.
通讯作者：
Vincent, John B.