Wang Ruixiang, Hausknecht Kathryn, Shen Roh-Yu, Haj-Dahmane Samir
Research Institute on Addictions, University at Buffalo, The State University of New York, Buffalo, NY, United States.
Department of Psychology, University at Buffalo, The State University of New York, Buffalo, NY, United States.
Front Pharmacol. 2018 Oct 16;9:1185. doi: 10.3389/fphar.2018.01185. eCollection 2018.
Autism spectrum disorder (ASD) is characterized by social and communicative impairments and increased repetitive behaviors. These symptoms are often comorbid with increased anxiety. Prenatal exposure to valproic acid (VPA), an anti-seizure and mood stabilizer medication, is a major environmental risk factor of ASD. Given the important role of the serotonergic (5-HT) system in anxiety, we examined the impact of prenatal VPA exposure on the function of dorsal raphe nucleus (DRn) 5-HT neurons. We found that male rats prenatally exposed to VPA exhibited increased anxiety-like behaviors revealed by a decreased time spent on the open arms of the elevated plus maze. Prenatal VPA exposed rats also exhibited a stereotypic behavior as indicated by excessive self-grooming in a novel environment. These behavioral phenotypes were associated with increased electrical activity of putative DRn 5-HT neurons recorded . Examination of underlying mechanisms revealed that prenatal VPA exposure increased excitation/inhibition ratio in synapses onto these neurons. The effect was mainly mediated by enhanced glutamate but not GABA release. We found reduced paired-pulse ratio (PPR) of evoked excitatory postsynaptic currents (EPSCs) and increased frequency but not amplitude of miniature EPSCs in VPA exposed rats. On the other hand, presynaptic GABA release did not change in VPA exposed rats, as the PPR of evoked inhibitory postsynaptic currents was unaltered. Furthermore, the spike-timing-dependent long-term potentiation at the glutamatergic synapses was occluded, indicating glutamatergic synaptic transmission is maximized. Lastly, VPA exposure did not alter the intrinsic membrane properties of DRn 5-HT neurons. Taken together, these results indicate that prenatal VPA exposure profoundly enhances glutamatergic synaptic transmission in the DRn and increases spontaneous firing in DRn 5-HT neurons, which could lead to increased serotonergic tone and underlie the increased anxiety and stereotypy after prenatal VPA exposure.
自闭症谱系障碍（ASD）的特征是社交和沟通障碍以及重复行为增加。这些症状常与焦虑增加并存。产前接触丙戊酸（VPA），一种抗癫痫和情绪稳定剂药物，是ASD的主要环境风险因素。鉴于血清素能（5-HT）系统在焦虑中的重要作用，我们研究了产前VPA暴露对中缝背核（DRn）5-HT神经元功能的影响。我们发现，产前接触VPA的雄性大鼠表现出焦虑样行为增加，这通过高架十字迷宫开放臂上停留时间减少得以体现。产前接触VPA的大鼠在新环境中过度自我梳理，也表现出刻板行为。这些行为表型与记录的假定DRn 5-HT神经元电活动增加有关。对潜在机制的研究表明，产前VPA暴露增加了这些神经元突触的兴奋/抑制比。这种效应主要由谷氨酸释放增强介导，而非GABA释放。我们发现，在接触VPA的大鼠中，诱发兴奋性突触后电流（EPSCs）的配对脉冲比率（PPR）降低，微小EPSCs的频率增加但幅度未变。另一方面，接触VPA的大鼠突触前GABA释放没有变化，因为诱发抑制性突触后电流的PPR未改变。此外，谷氨酸能突触处的尖峰时间依赖性长期增强被阻断，表明谷氨酸能突触传递已达到最大值。最后，VPA暴露并未改变DRn 5-HT神经元的内在膜特性。综上所述，这些结果表明，产前VPA暴露深刻增强了DRn中的谷氨酸能突触传递，并增加了DRn 5-HT神经元中的自发放电，这可能导致血清素能张力增加，并成为产前VPA暴露后焦虑和刻板行为增加的基础。
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