Synaptic protein expression in bipolar disorder patient-derived neurons implicates PSD-95 as a marker of lithium response

IF 4.6 2区 医学 Q1 NEUROSCIENCES Neuropharmacology Pub Date : 2025-01-15 DOI:10.1016/j.neuropharm.2025.110313
Kayla E. Rohr , Himanshu K. Mishra , Johansen Amin , Timothy Nakhla , Michael J. McCarthy
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Abstract

Bipolar disorder (BD) is a severe mental illness characterized by recurrent episodes of depression and mania. Lithium is the gold standard pharmacotherapy for BD, but outcomes are variable, and the relevant therapeutic mechanisms underlying successful treatment response remain uncertain. To identify synaptic markers of BD and lithium response, we measured the effects of lithium on induced pluripotent stem cell-derived neurons from BD patients and controls. We determined that baseline expression of synapsin I (SYN1) and PSD-95 is reduced in BD neurons compared to controls. In control neurons, lithium treatment had modest, transient effects increasing SYN1 and PSD-95 expression. In BD neurons, lithium increased SYN1 expression regardless of lithium response history. However, lithium only increased PSD-95 expression selectively in neurons from lithium-responders and not in neurons from lithium non-responders, leading to group differences in the colocalization of SYN1 and PSD-95. In conclusion, this preliminary work indicates synaptic protein markers are associated with BD pathology and correction of post-synaptic protein expression may be an important mechanism underlying lithium response.
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双相情感障碍患者源性神经元突触蛋白表达暗示PSD-95是锂反应的标志物。
双相情感障碍(BD)是一种严重的精神疾病,其特征是反复发作的抑郁和躁狂。锂是双相障碍的金标准药物治疗,但结果是可变的,成功治疗反应的相关治疗机制仍然不确定。为了确定BD和锂反应的突触标志物,我们测量了锂对BD患者和对照组诱导多能干细胞来源的神经元的影响。我们确定,与对照组相比,BD神经元中突触素I (SYN1)和PSD-95的基线表达减少。在对照神经元中,锂处理对SYN1和PSD-95的表达有轻微的、短暂的影响。在BD神经元中,无论锂反应历史如何,锂都增加了SYN1的表达。然而,锂只选择性地增加了锂应答者神经元中PSD-95的表达,而非锂应答者神经元中PSD-95的表达,导致SYN1和PSD-95共定位的组间差异。总之,这项初步工作表明突触蛋白标记物与BD病理相关,突触后蛋白表达的纠正可能是锂反应的重要机制。
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来源期刊
Neuropharmacology
Neuropharmacology 医学-神经科学
CiteScore
10.00
自引率
4.30%
发文量
288
审稿时长
45 days
期刊介绍: Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).
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