Perez Stephanie M, Donegan Jennifer J, Lodge Daniel J
UT Health San Antonio, Department of Pharmacology, Center for Biomedical Neuroscience, 7703 Floyd Curl Drive, MC 7764, San Antonio, TX, 78229, USA.
Behav Brain Res. 2019 Apr 19;362:258-265. doi: 10.1016/j.bbr.2019.01.031. Epub 2019 Jan 17.
Although there are clear sex differences in individuals with schizophrenia, preclinical research has historically favored the use of male rats for behavioral studies. The methylazoxymethanol acetate (MAM) model is a gestational disruption model of schizophrenia and has been reported to produce robust behavioral, neurophysiological and anatomical alterations in male rats; however, whether similar effects are observed in female rats is less well known. In this study, we characterize the behavioral, electrophysiological and molecular alterations induced by prenatal MAM administration in female rats while also examining the potential effects of the estrous cycle on schizophrenia-like behaviors. Specifically, MAM-treated female offspring demonstrated deficits in sensorimotor gating, latent inhibition, and social interaction, consistent with those observed in male animals. Interestingly, amphetamine-induced locomotor activity, latent inhibition, and social interaction were also affected by the estrous cycle. To examine the potential cellular mechanisms associated with these behavioral alterations, we analyzed hippocampal parvalbumin (PV) interneurons. Deficits in PV interneuron number and high-frequency gamma oscillations were disrupted in female MAM-treated rats regardless of the stage of the estrous cycle; however, alterations in PV protein expression were more prominent during metestrus/diestrus. Taken together, these data suggest that prenatal MAM exposure in female rats produces robust behavioral, molecular, and physiological deficits consistent with those observed in the male MAM model of schizophrenia. Moreover, our results also suggest that specific schizophrenia-like symptoms can also be influenced by the estrous cycle, and further emphasize the importance of sex as a biological variable when using preclinical models.
虽然精神分裂症患者存在明显的性别差异，但临床前研究历来倾向于使用雄性大鼠进行行为研究。醋酸甲基氧化偶氮甲醇（MAM）模型是一种精神分裂症的孕期干扰模型，据报道，该模型会在雄性大鼠身上产生显著的行为、神经生理和解剖学改变；然而，雌性大鼠是否会出现类似效应却鲜为人知。在本研究中，我们描述了产前给予MAM对雌性大鼠诱导的行为、电生理和分子改变，同时还研究了发情周期对精神分裂症样行为的潜在影响。具体而言，经MAM处理的雌性后代在感觉运动门控、潜伏抑制和社交互动方面表现出缺陷，这与在雄性动物中观察到的情况一致。有趣的是，安非他明诱导的运动活动、潜伏抑制和社交互动也受发情周期影响。为了研究与这些行为改变相关的潜在细胞机制，我们分析了海马小白蛋白（PV）中间神经元。无论发情周期处于哪个阶段，经MAM处理的雌性大鼠的PV中间神经元数量和高频伽马振荡的缺陷均受到破坏；然而，PV蛋白表达的改变在动情后期/间情期更为明显。综上所述，这些数据表明，雌性大鼠产前暴露于MAM会产生与雄性MAM精神分裂症模型中观察到的一致的显著行为、分子和生理缺陷。此外，我们的结果还表明，特定的精神分裂症样症状也会受到发情周期的影响，并进一步强调了在使用临床前模型时性别作为生物学变量的重要性。
