Wang Ziyi Zephyr, Folorunso Oluwarotimi O, Morris Kiely, Berretta Sabina, Engin Elif
Stress Neurobiology Laboratory, Division of Basic Neuroscience, McLean Hospital, Belmont, MA, United States.
Department of Psychiatry, Harvard Medical School, Boston, MA, United States.
Front Neurosci. 2024 Dec 12;18:1445162. doi: 10.3389/fnins.2024.1445162. eCollection 2024.
The expression of GABARs goes through large scale, evolutionarily conserved changes through the early postnatal period. While these changes have been well-studied in brain regions such as the hippocampus and sensory cortices, less is known about early developmental changes in other brain areas. The nucleus accumbens (NAc) is a major hub in the circuitry that mediates motivated behaviors and disruptions in NAc activity is a part of the neuropathology observed in mood and substance use disorders. Considering the importance of early developmental disruptions in the vulnerability to and etiology of these disorders, it is essential to understand normal developmental changes in the NAc as a first step to understanding how these changes might be disrupted to cause long-term pathology. Here, we aimed to address the gap in knowledge of early developmental changes in GABAR expression in NAc neurons. We investigated the expression patterns of GABAR α1, α2, and α4 subunits in Drd1+, Drd2+, and putative hybrid medium spiny neurons (MSNs) of the mouse NAc over a developmental window from P2 to P16. Our findings show a consistent increase in expression of all 3 GABAR subunits in Drd1+ MSNs, accompanied by stable expression or even a decrease in expression in Drd2+ MSNs. The putative hybrid population showed a complex expression pattern, usually showing maximum expression at P9. These early developmental changes likely suggest a specific window where GABAR expression patterns adjust to increasing glutamatergic inputs from external sources, changes in intracellular chloride concentrations, and a switch towards the mature, bistable activity patterns of MSNs from the immature, relatively excitable singular pattern. We propose that this time of dynamic changes in GABAR expression could represent a sensitive period during which developmental insults might lead to permanent disruptions in GABAR expression patterns.
在出生后早期，GABARs的表达经历了大规模的、进化上保守的变化。虽然这些变化在海马体和感觉皮层等脑区已得到充分研究，但对于其他脑区的早期发育变化了解较少。伏隔核（NAc）是介导动机行为的神经回路中的一个主要枢纽，NAc活动的破坏是在情绪和物质使用障碍中观察到的神经病理学的一部分。考虑到早期发育破坏在这些障碍的易感性和病因学中的重要性，了解NAc中的正常发育变化作为理解这些变化如何被破坏以导致长期病理学的第一步至关重要。在这里，我们旨在填补NAc神经元中GABAR表达早期发育变化知识的空白。我们研究了从P2到P16的发育窗口期间，小鼠NAc中Drd1 +、Drd2 +和假定的混合中型多棘神经元（MSNs）中GABAR α1、α2和α4亚基的表达模式。我们的研究结果表明，Drd1 + MSNs中所有3种GABAR亚基的表达持续增加，而Drd2 + MSNs中的表达则稳定或甚至下降。假定的混合群体表现出复杂的表达模式，通常在P9时表达最高。这些早期发育变化可能表明一个特定的窗口，在此期间GABAR表达模式适应来自外部来源的谷氨酸能输入增加、细胞内氯离子浓度的变化，以及从中型多棘神经元不成熟的、相对易兴奋的单一模式向成熟的双稳态活动模式的转变。我们提出，GABAR表达的这种动态变化时期可能代表一个敏感期，在此期间发育损伤可能导致GABAR表达模式的永久性破坏。
