Szumlinski Karen K, Datko Michael C, Lominac Kevin D, Jentsch J David
Department of Psychological and Brain Sciences, University of California Santa Barbara, Santa Barbara, CA 93106, USA.
Department of Molecular, Cellular and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA 93106, USA.
Int J Mol Sci. 2024 Nov 27;25(23):12732. doi: 10.3390/ijms252312732.
Elevated risk for schizophrenia is associated with a variation in the gene encoding dysbindin-1, which may underpin cognitive impairments in this prevalent neuropsychiatric disorder. The cognitive symptoms of schizophrenia involve anomalies in glutamate and dopamine signaling, particularly within the prefrontal cortex (PFC). Indeed, mice with mutations exhibit spatial and working memory deficits that are associated with deficits in glutamate release and NMDA receptor function as determined by slice electrophysiology. The present study extended the results from ex vivo approaches by examining how the mutation impacts high K+- and NMDA receptor-evoked glutamate release within the PFC using in vivo microdialysis procedures. mutant mice are also reported to exhibit blunted K+-evoked dopamine release within the PFC. Thus, we examined also K+- and NMDA-evoked dopamine release within this region. Perfusion of high-concentration K+ or NMDA solutions increased the PFC levels of both dopamine and glutamate in wild-type (WT) but not in mutants (MUT), whereas mice heterozygous for the mutation (HET) exhibited blunted K+-evoked dopamine release. No net-flux microdialysis procedures confirmed elevated basal extracellular content of both glutamate and dopamine within the PFC of HET and MUT mice. These in vivo microdialysis results corroborate prior indications that mutations perturb evoked dopamine and glutamate release within the PFC, provide in vivo evidence for impaired NMDA receptor function within the PFC, and suggest that these neurochemical anomalies may be related to abnormally elevated basal neurotransmitter content.
精神分裂症风险升高与编码失调素-1的基因变异有关，这可能是这种常见神经精神疾病认知障碍的基础。精神分裂症的认知症状涉及谷氨酸和多巴胺信号传导异常，尤其是在前额叶皮质（PFC）内。实际上，携带突变的小鼠表现出空间和工作记忆缺陷，切片电生理学研究表明这些缺陷与谷氨酸释放和NMDA受体功能缺陷有关。本研究通过使用体内微透析程序检查突变如何影响PFC内高K +和NMDA受体诱发的谷氨酸释放，扩展了体外研究结果。据报道，突变小鼠在PFC内K +诱发的多巴胺释放也减弱。因此，我们还检查了该区域内K +和NMDA诱发的多巴胺释放。灌注高浓度K +或NMDA溶液可增加野生型（WT）小鼠PFC中多巴胺和谷氨酸的水平，但突变型（MUT）小鼠则不然，而杂合突变（HET）小鼠表现出K +诱发的多巴胺释放减弱。无净通量微透析程序证实HET和MUT小鼠PFC内谷氨酸和多巴胺的基础细胞外含量升高。这些体内微透析结果证实了先前的迹象，即突变会扰乱PFC内诱发的多巴胺和谷氨酸释放，为PFC内NMDA受体功能受损提供了体内证据，并表明这些神经化学异常可能与基础神经递质含量异常升高有关。
