Midbrain Gene Screening Identifies a New Mesoaccumbal Glutamatergic Pathway and a Marker for Dopamine Cells Neuroprotected in Parkinson’s Disease

Abstract

The ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) of the midbrain are associated with Parkinson’s disease (PD), schizophrenia, mood disorders and addiction. Based on the recently unraveled heterogeneity within the VTA and SNc, where glutamate, GABA and co-releasing neurons have been found to co-exist with the classical dopamine neurons, there is a compelling need for identification of gene expression patterns that represent this heterogeneity and that are of value for development of human therapies. Here, several unique gene expression patterns were identified in the mouse midbrain of which NeuroD6 and Grp were expressed within different dopaminergic subpopulations of the VTA, and TrpV1 within a small heterogeneous population. Optogenetics-coupled in vivo amperometry revealed a previously unknown glutamatergic mesoaccumbal pathway characterized by TrpV1-Cre-expression. Human GRP was strongly detected in non-melanized dopaminergic neurons within the SNc of both control and PD brains, suggesting GRP as a marker for neuroprotected neurons in PD. This study thus unravels markers for distinct subpopulations of neurons within the mouse and human midbrain, defines unique anatomical subregions within the VTA and exposes an entirely new glutamatergic pathway. Finally, both TRPV1 and GRP are implied in midbrain physiology of importance to neurological and neuropsychiatric disorders.

Transcriptome responses to reduced dopamine in the Substantia Nigra Pars Compacta reveals a potential protective role for dopamine

“…Nurr1 null mice die within 24h after birth and conditional knockout of Nr4a2 in DA neurons in adult animals caused decreased expression of DA markers, including Th and Slc6a3 (DAT), followed by progressive loss of DA (Castillo et al 1998;Kadkhodaei et al 2009Kadkhodaei et al , 2013 (Chang et al 2019;Lindefors and Ungerstedt 1990;Rodríguez-Puertas et al 1999). There are additional levels of crosstalk between glutamate and dopamine-glutamate neurons and their local synapses within the midbrain DA regions (Dobi et al 2010;Morales and Root 2014;Viereckel et al 2016;Wang and Morales 2009;Yamaguchi et al 2015). In our study we detect increased levels of metabotropic glutamate receptor 1 and ionotropic glutamate receptor NMDA 3A.…”

Single-Cell RNA-Seq of Mouse Dopaminergic Neurons Informs Candidate Gene Selection for Sporadic Parkinson Disease

“…47,50 In addition, we identified four P7 MB DA subset clusters ( Figure 2D). Marker gene analysis confirmed that three of the clusters correspond to DA neurons from the VTA (Otx2 and Neurod6; P7.MB.1), 51,52 the periaqueductal gray area (PAG; Vip and Pnoc; P7.MB.3), 53,54 and the SN (Sox6, Aldh1a7, Ndnf, Serpine2, Rbp4, and Fgf20; P7.MB.4) 38,51,55,56 (Tables 1, S2, and S3). These data are consistent with recent scRNA-seq studies of similar populations.…”

Validated multi‐step approach for in vivo recording and analysis of optogenetically evoked glutamate in the mouse globus pallidus

“…) and we have recently reported the possibility to record glutamate release in the nucleus accumbens following optogenetic stimulation (Viereckel et al . ; Wang et al . ).…”