Alterations of Striatal Projection Neurons in Parkinson's disease

National Institute On Aging

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Abstract

To investigate potential anatomical changes in striosome SPNs in Pitx3ak/ak mice, we performed crossbreeding between two distinct striosome SPN reporter mouse lines, Nr4a1-GFP68 and Sepw1-Cre/Ai27D, into the Pitx3ak/ak background. Subsequently, we examined the projections of striosome SPNs to different target brain regions. Remarkably, both the Nr4a1-GFP/Pitx3ak/ak and Sepw1-Cre/Ai27D/Pitx3ak/ak lines exhibited a substantial reduction in the striosomal projection to the substantia nigra pars reticulata (SNr) and an increase in projection to the globus pallidus externa (GPe) compared to control mice. As the striosome dSPNs project to the SNr and iSPNs project to the GPe, these observations suggest a reduction in striosome dSPN numbers and an increase in iSPN numbers in Pitx3ak/ak mice. Supporting this notion, our RNAscope in situ hybridization experiments further revealed a significant decrease in the number of striosome dSPNs and a relative increase in striosome iSPNs in Pitx3ak/ak mice. Taken together, these findings demonstrate the reconfiguration of striosome SPN subtypes in response to PD-like dopamine depletion, leading to a shift in dominance from the striosome direct pathway to the indirect pathway. To delve deeper into gene expression changes at the single-cell level in the striatum of Pitx3ak/ak mice, we conducted single nuclei RNA sequencing (snRNAseq) on striatal tissues isolated from Pitx3ak/ak and littermate control mice. Preliminary analyses of the snRNAseq data supported the early findings from the RNAscope and immunostaining studies. Notably, Pitx3ak/ak mice exhibited significant impairments in the rotarod motor skill learning task69. To explore potential alterations in neuronal activity in striosome dSPNs and iSPNs, we utilized an intersectional mouse genetics approach to generate Cre and Flp DNA recombinase dual-controlled mice, enabling specific genetic manipulation of striosome dSPNs and iSPNs. Using two-photon imaging and fiber photometry, we recorded neuronal activity from these specific subpopulations during motor skill learning. Additionally, we employed optogenetics or chemogenetics to rebalance the activity of striosome dSPNs and iSPNs, aiming to rescue the motor learning impairments observed in Pitx3ak/ak mice. Furthermore, we will extend the findings from Pitx3ak/ak mice to investigate other PD-related mouse models that experience age-dependent loss of SNc DANs. This will help us determine whether the remodeling of striosome direct and indirect pathway neurons is a common phenomenon in such mouse models. The collective insights gained from these studies will contribute to a better understanding of the pathogenetic mechanisms of striatal neurons in PD.