Patton Mary H, Teubner Brett J W, Thomas Kristen T, Freshour Sharon L, Trevisan Alexandra J, Schild Andrew B, Ramirez Cody A, Bikoff Jay B, Zakharenko Stanislav S
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
bioRxiv. 2025 Jun 21:2025.06.20.660782. doi: 10.1101/2025.06.20.660782.
Schizophrenia is a complex neurodevelopmental disorder characterized by cognitive dysfunction, hallucinations, and negative symptoms such as amotivation. Negative symptoms are largely resistant to current antipsychotic treatments, and the neural circuits underlying amotivational states remain poorly defined. Here, using a mouse model of schizophrenia-associated 22q11.2 deletion syndrome (22q11DS), we report amotivation and weakened glutamatergic synaptic transmission between the thalamic parafascicular nucleus (Pf) and the dorsomedial striatum (DMS). Thalamostriatal disruption is attributed to hyperactivity of striatal cholinergic interneurons (CHIs), which is associated with enhanced and () gene expression. Elevated acetylcholine levels in the DMS act on presynaptic M2 muscarinic receptors to weaken Pf-DMS glutamatergic transmission. Importantly, disruption of Pf-DMS synaptic transmission or hyperactivation of CHIs are each sufficient to cause amotivation in wild-type mice. These results identify a striatal hypercholinergic state and subsequent thalamostriatal disruption as core pathogenic events causing amotivation in 22q11DS, providing potential therapeutic targets.
精神分裂症是一种复杂的神经发育障碍，其特征为认知功能障碍、幻觉以及诸如缺乏动机等阴性症状。阴性症状在很大程度上对当前的抗精神病药物治疗具有抗性，并且缺乏动机状态背后的神经回路仍未得到很好的界定。在此，我们使用与精神分裂症相关的22q11.2缺失综合征（22q11DS）小鼠模型，报告了缺乏动机以及丘脑束旁核（Pf）与背内侧纹状体（DMS）之间谷氨酸能突触传递减弱的情况。丘脑纹状体功能紊乱归因于纹状体胆碱能中间神经元（CHIs）的活动亢进，这与增强的（）基因表达相关。DMS中升高的乙酰胆碱水平作用于突触前M2毒蕈碱受体，以减弱Pf-DMS谷氨酸能传递。重要的是，Pf-DMS突触传递的破坏或CHIs的过度激活各自足以在野生型小鼠中导致缺乏动机。这些结果确定了纹状体高胆碱能状态以及随后的丘脑纹状体功能紊乱是导致22q11DS中缺乏动机的核心致病事件，提供了潜在的治疗靶点。
