Chemogenetic activation and inhibition of CaMKⅡα-positive neurons in the dorsal hippocampus modulate spatial working memory and hippocampus-dependent memory in the hemiparkinsonian rat.
Parkinson's disease (PD) is frequently associated with cognitive impairments, especially deficits in working memory and hippocampus-dependent memory. However, the contribution of dorsal hippocampus (dHipp) Ca2+/calmodulin-dependent protein kinase Ⅱ α (CaMKⅡα)-positive neurons to these deficits remains unclear. In this study, we investigated the impacts of chemogenetic modulation of dHipp CaMKⅡα-positive neurons on cognitive function, hippocampal theta rhythm, and monoamine levels in both sham-operated and unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats. 6-OHDA lesions of the medial forebrain bundle impaired spatial working memory and hippocampus-dependent memory, reduced the peak theta frequency in the dHipp, and decreased dopamine levels in the striatum, medial prefrontal cortex (mPFC), dHipp and ventral hippocampus (vHipp). In sham-operated rats, chemogenetic manipulation of dHipp CaMKⅡα-positive neurons did not alter memory performance or theta rhythm. Aside from an increase in dopamine levels in the mPFC following activation, chemogenetic manipulation had no effect on monoamines. In contrast, in the 6-OHDA-lesioned rats, activation of dHipp CaMKⅡα-positive neurons improved spatial working memory and hippocampus-dependent memory, increased the peak theta frequency in the dHipp, and elevated dopamine levels in the mPFC, dHipp and vHipp, whereas inhibition exacerbated cognitive deficits, reduced the peak theta frequency in the dHipp, and decreased the level of noradrenaline in the above brain regions. These findings suggest that activation or inhibition of dHipp CaMKⅡα-positive neurons exerts opposing effects on cognitive function specifically in parkinsonian rats, which may be associated with alterations in hippocampal theta oscillations and monoaminergic transmission. Targeting dHipp CaMKⅡα-positive neurons may offer a promising therapeutic strategy for cognitive symptoms in PD.