Pershing Michelle L, Bortz David M, Pocivavsek Ana, Fredericks Peter J, Jørgensen Christinna V, Vunck Sarah A, Leuner Benedetta, Schwarcz Robert, Bruno John P
Department of Psychology, The Ohio State University, Columbus, OH, USA.
Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland College of Medicine, Baltimore, MD, USA.
Neuropharmacology. 2015 Mar;90:33-41. doi: 10.1016/j.neuropharm.2014.10.017. Epub 2014 Nov 1.
The levels of kynurenic acid (KYNA), an endogenous negative modulator of alpha7 nicotinic acetylcholine receptors (α7nAChRs), are elevated in the brains of patients with schizophrenia (SZ). We reported that increases of brain KYNA in rats, through dietary exposure to its precursor kynurenine from embryonic day (ED)15 to postnatal day (PD) 21, result in neurochemical and cognitive deficits in adulthood. The present experiments focused on the effects of prenatal exposure to elevated kynurenine on measures of prefrontal excitability known to be impaired in SZ. Pregnant dams were fed a mash containing kynurenine (100 mg/day; progeny = EKYNs) from ED15 until ED22. Controls were fed an unadulterated mash (progeny = ECONs). The dietary loading procedure elevated maternal and fetal plasma kynurenine (2223% and 693% above controls, respectively) and increased fetal KYNA (forebrain; 500% above controls) on ED21. Elevations in forebrain KYNA disappeared after termination of the loading (PD2), but KYNA levels in the prefrontal cortex (PFC) were unexpectedly increased again when measured in adults (PD56-80; 75% above controls). We also observed changes in several markers of prefrontal excitability, including expression of the α7nAChR (22% and 17% reductions at PD2 and PD56-80), expression of mGluR2 (31% and 24% reductions at ED21 and PD56-80), dendritic spine density (11-14% decrease at PD56-80), subsensitive mesolimbic stimulation of glutamate release in PFC, and reversal/extra-dimensional shift deficits in the prefrontally-mediated set-shifting task. These results highlight the deleterious impact of elevated KYNA levels during sensitive periods of early development, which model the pathophysiological and cognitive deficits seen in SZ.
犬尿喹啉酸（KYNA）是α7烟碱型乙酰胆碱受体（α7nAChRs）的内源性负性调节剂，其在精神分裂症（SZ）患者大脑中的水平会升高。我们曾报道，从胚胎期第15天（ED15）到出生后第21天（PD21），通过饮食让大鼠接触KYNA的前体犬尿氨酸，会导致成年大鼠出现神经化学和认知缺陷。本实验着重研究产前暴露于高剂量犬尿氨酸对已知在SZ中受损的前额叶兴奋性指标的影响。怀孕母鼠从ED15到ED22被喂食含犬尿氨酸的混合饲料（100毫克/天；后代 = EKYNs）。对照组喂食未掺杂的混合饲料（后代 = ECONs）。饮食加载程序使母体和胎儿血浆犬尿氨酸水平升高（分别比对照组高2223%和693%），并使ED21时胎儿的KYNA升高（前脑；比对照组高500%）。加载结束后（PD2）前脑KYNA升高消失，但在成年期（PD56 - 80）测量时，前额叶皮质（PFC）中的KYNA水平意外再次升高（比对照组高75%）。我们还观察到前额叶兴奋性的几个标志物发生了变化，包括α7nAChR的表达（在PD2和PD56 - 80分别降低22%和17%）、代谢型谷氨酸受体2（mGluR2）的表达（在ED21和PD56 - 80分别降低31%和24%）、树突棘密度（在PD56 - 80降低11 - 14%）、PFC中谷氨酸释放的中脑边缘刺激反应迟钝，以及前额叶介导的定势转换任务中的反转/维度外转换缺陷。这些结果突出了早期发育敏感期KYNA水平升高的有害影响，这种影响模拟了SZ中出现的病理生理和认知缺陷。
