METHODS: We identified a series of synaptic alterations of the lateral and medial perforant paths in animals postnatally treated with the NMDA antagonist MK-801. This dysregulation suggests decreased cognitive performance, for which the dentate gyrus is critical.
RESULTS: We identified alterations in the synaptic properties of the lateral and medial perforant paths to the dentate gyrus synapses in slices from MK-801-treated animals. Altered glutamate release and decreased synaptic strength precede an impairment in the induction and expression of long-term potentiation (LTP) and CB1 receptor-mediated long-term depression (LTD). Remarkably, by inhibiting the degradation of 2-arachidonoylglycerol (2-AG), an endogenous ligand of the CB1 receptor, we restored the LTD in animals treated with MK-801. Additionally, we showed for the first time, that spatial discrimination, a cognitive task that requires dentate gyrus integrity, is impaired in animals exposed to transient hypofunction of NMDA receptors.
CONCLUSIONS: Dysregulation of glutamatergic transmission and synaptic plasticity from the entorhinal cortex to the dentate gyrus has been demonstrated, which may explain the cellular dysregulations underlying the altered cognitive processing in the dentate gyrus associated with schizophrenia.
方法:我们发现了一系列用NMDA拮抗剂MK-801治疗的动物的外侧和内侧穿孔路径的突触改变。这种失调表明认知能力下降,齿状回对此至关重要。
结果:我们确定了MK-801处理动物切片中齿状回突触的外侧和内侧穿通路径的突触特性的改变。谷氨酸释放的改变和突触强度的降低先于长期增强(LTP)和CB1受体介导的长期抑郁症(LTD)的诱导和表达受损。值得注意的是,通过抑制2-花生四酰基甘油(2-AG)的降解,CB1受体的内源性配体,我们在用MK-801治疗的动物中恢复了LTD。此外,我们第一次展示,空间歧视,一项需要齿状回完整性的认知任务,在暴露于NMDA受体短暂功能减退的动物中受损。
结论:已经证明了从内嗅皮层到齿状回的谷氨酸能传递和突触可塑性的失调,这可以解释与精神分裂症相关的齿状回认知过程改变背后的细胞失调。