Department of Psychiatry, Indiana University School of Medicine, 1111 W. 10th St. Indianapolis, IN 46202, USA.
Int J Psychophysiol. 2012 Nov;86(2):136-42. doi: 10.1016/j.ijpsycho.2012.04.002. Epub 2012 Apr 12.
Alterations in neural synchrony and oscillations may contribute to the pathophysiology of schizophrenia and reflect aberrations in cortical glutamatergic and GABAergic neurotransmission. We tested the effects of a GABA agonist and an NMDA antagonist on auditory steady state responses (ASSRs) in awake rats with neonatal ventral hippocampal lesions (NVHLs) as a neurodevelopmental model of schizophrenia. NVHL vs. SHAM lesioned rats were injected with saline then either ketamine (NMDA antagonist) or muscimol (GABA(A) agonist). Time-frequency analyses examined alterations in phase locking (consistency) across trials and changes in total power (magnitude). ASSRs were compared at five stimulation frequencies (10, 20, 30, 40, and 50 Hz). In SHAM rats, phase locking and power generally increased with stimulation frequency. Both ketamine and muscimol also increased phase locking and power in SHAM rats, but mostly in the 20 to 40 Hz range. NVHL and ketamine altered the frequency dependence of phase locking, while only ketamine changed power frequency dependence. Muscimol affected power, but not phase locking, in the NVHL rats. NVHL and ketamine models of schizophrenia produce similar independent effects on ASSR, potentially representing similar forms of cortical network/glutamatergic dysfunction, albeit the effects of ketamine were more robust. Muscimol produced NVHL-dependent reductions in ASSR measures, suggesting that cortical networks in this model are intolerant to post-synaptic GABAergic stimulation. These findings suggest the utility of combining lesion, pharmacological, and ASSR approaches in understanding neural mechanisms underlying disturbed synchrony in schizophrenia.
神经同步和振荡的改变可能有助于精神分裂症的病理生理学，并反映皮质谷氨酸能和 GABA 能神经传递的异常。我们测试了 GABA 激动剂和 NMDA 拮抗剂对新生海马腹侧损伤（NVHL）大鼠听觉稳态反应（ASSR）的影响，作为精神分裂症的神经发育模型。NVHL 与 SHAM 损伤大鼠分别用生理盐水或氯胺酮（NMDA 拮抗剂）或 muscimol（GABA(A)激动剂）注射。时频分析检查了跨试验的相位锁定（一致性）的变化和总功率（幅度）的变化。ASSR 在五个刺激频率（10、20、30、40 和 50 Hz）下进行比较。在 SHAM 大鼠中，相位锁定和功率通常随刺激频率而增加。氯胺酮和 muscimol 也增加了 SHAM 大鼠的相位锁定和功率，但主要在 20 到 40 Hz 范围内。NVHL 和氯胺酮改变了相位锁定的频率依赖性，而只有氯胺酮改变了功率频率依赖性。mucimol 影响了 NVHL 大鼠的功率，但不影响相位锁定。精神分裂症的 NVHL 和氯胺酮模型对 ASSR 产生了类似的独立影响，可能代表了类似的皮质网络/谷氨酸能功能障碍形式，尽管氯胺酮的影响更为显著。mucimol 导致 ASSR 测量值的 NVHL 依赖性降低，表明该模型中的皮质网络对突触后 GABA 能刺激不耐受。这些发现表明，结合损伤、药理学和 ASSR 方法来理解精神分裂症中同步紊乱的神经机制是有用的。
