Healey Kati L, Bell Amelia, Scofield Michael D, Swartzwelder H S
Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, N.C. 27710, United States of America.
Department of Anesthesia and Perioperative Medicine, Medical University of South Carolina, Charleston, S.C. 29425, United States of America.
Addict Neurosci. 2022 Dec;4. doi: 10.1016/j.addicn.2022.100047. Epub 2022 Nov 9.
Alcohol consumption in adolescence causes multiple acute negative changes in neural and behavioral function that persist well into adulthood and possibly throughout life. The medial prefrontal cortex (mPFC) and dorsal hippocampus are critical for executive function and memory and are especially vulnerable to adolescent ethanol exposure. We have reported that astrocytes, particularly in the mPFC, change both in morphology and synaptic proximity during adolescence. Moreover, adolescent intermittent ethanol (AIE) exposure produces enduring effects on both astrocyte function and synaptic proximity in the adult hippocampal formation, and the latter effect was reversed by the clinically used agent gabapentin (Neurontin), an anticonvulsant and analgesic that is an inhibitor of the VGCC 21 subunit. These findings underscore the importance of investigating AIE effects on astrocytes in the mPFC, a region that undergoes marked changes in structure and connectivity during adolescence. Using astrocyte-specific viral labeling and immunohistochemistry, mPFC astrocytic morphology and colocalization with AMPA-(-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) glutamate receptor 1 (GluA1), an AMPA receptor subunit and established neuronal marker of excitatory synapses, were assessed to quantify the proximity of astrocyte processes with glutamatergic synaptic puncta. AIE exposure significantly reduced astrocyte-synaptic proximity in adulthood, an effect that was reversed by sub-chronic gabapentin treatment in adulthood. There was no effect of AIE on astrocytic glutamate homeostasis machinery or neuronal synaptic proteins in the mPFC. These findings indicate a possible glial-neuronal mechanism underlying the effects of AIE on frontal lobe-mediated behaviors and suggest a specific therapeutic approach for the amelioration of those effects.
青少年饮酒会导致神经和行为功能出现多种急性负面变化，这些变化会持续到成年期，甚至可能终生存在。内侧前额叶皮质（mPFC）和背侧海马体对执行功能和记忆至关重要，特别容易受到青少年乙醇暴露的影响。我们已经报道，星形胶质细胞，尤其是mPFC中的星形胶质细胞，在青春期会发生形态和突触接近度的变化。此外，青少年间歇性乙醇（AIE）暴露会对成年海马结构中的星形胶质细胞功能和突触接近度产生持久影响，而临床使用的抗惊厥和镇痛药加巴喷丁（Neurontin，一种电压门控钙通道21亚基的抑制剂）可逆转后一种影响。这些发现强调了研究AIE对mPFC中星形胶质细胞影响的重要性，mPFC是一个在青春期结构和连接性会发生显著变化的区域。使用星形胶质细胞特异性病毒标记和免疫组织化学方法，评估了mPFC星形胶质细胞的形态以及与AMPA-（α-氨基-3-羟基-5-甲基-4-异恶唑丙酸）谷氨酸受体1（GluA1，一种AMPA受体亚基和兴奋性突触已确定的神经元标记物）的共定位，以量化星形胶质细胞突起与谷氨酸能突触小点的接近程度。AIE暴露显著降低了成年期星形胶质细胞与突触的接近度，成年期亚慢性加巴喷丁治疗可逆转这一效应。AIE对mPFC中星形胶质细胞谷氨酸稳态机制或神经元突触蛋白没有影响。这些发现表明了一种可能的神经胶质-神经元机制，该机制是AIE对额叶介导行为产生影响的基础，并提出了一种改善这些影响的特定治疗方法。
