GluN2B in the dorsal hippocampus is involved in the regulation of hippocampus-dependent memory in Parkinsonian rats.

Cognitive impairment is one of the most common non-motor symptoms of Parkinson's disease (PD), which occurs even at an early stage and progresses over time. The hippocampus is involved in PD-related cognitive impairment and expresses abundant GluN2B-containing N-methyl-D-aspartic acid (NMDA) receptors. Until now, the role of hippocampal GluN2B in PD-related cognitive impairment remains unclear. In the present study, data-independent acquisition (DIA) proteomics and Western blotting revealed that unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc) resulted in decreased expression of GluN2B in the dorsal hippocampus (dHip), and this decrease in expression is strongly associated with PD-related cognitive impairment. In addition, we also found that unilateral SNc lesioning leads to hippocampus-dependent memory impairment, hypoactive delta activity, and hyperactive theta activity. Subsequently, intra-dHip injection of the GluN2B antagonist Ro 25-6981 impaired hippocampus-dependent memory in sham-operated and 6-OHDA-lesioned rats. Notably, the doses of Ro 25-6981 producing significant behavioral effects in 6-OHDA-lesioned rats were higher than those in sham-operated rats. Additionally, intra-dHip injection of 0.6 μg of Ro 25-6981 led to increased normalized delta power and decreased normalized theta power in the dHip in sham-operated rats, but did not affect oscillatory activities in 6-OHDA-lesioned rats. Collectively, our findings suggest that GluN2B in the dHip plays a positive role in hippocampus-dependent memory and regulates delta and theta oscillatory activities, and its down-regulation and dysfunction are associated with PD-related cognitive impairment.