Lack of Rhes Increases MDMA-Induced Neuroinflammation and Dopamine Neuron Degeneration: Role of Gender and Age.

Giulia Costa,Francesco Napolitano,Pier Porceddu,Micaela Morelli,Annalisa Pinna,Marcello Serra,Alessandro Usiello,Maria Casu,Valentina Schiano

doi:10.3390/ijms20071556

Abstract

Ras homolog enriched in striatum (Rhes) is a protein that exerts important physiological functions and modulates psychostimulant drug effects. On this basis, the object of this study was to assess 3,4-methylenedioxymethamphetamine (MDMA) effects on microglial (CD11b) and astroglial (GFAP) activation and on dopamine neuron degeneration (TH) in wild-type (WT) and Rhes knockout (KO) male and female mice of different ages. Motor activity was also evaluated. Adult (3 months) MDMA-treated mice displayed an increase in GFAP-positive cells in striatum (STR), whereas the substantia nigra pars compacta (SNc) was affected only in male mice. In these mice, the increase of CD11b was more extensive including STR, SNc, motor cortex (CTX), ventral tegmental area (VTA), and nucleus accumbens (NAc). MDMA administration also affected TH immunoreactivity in both STR and SNc of male but not female WT and Rhes KO mice. In middle-aged mice (12 months), MDMA administration further increased GFAP and CD11b and decreased TH immunoreactivity in STR and SNc of all mice. Finally, MDMA induced a higher increase of motor activity in adult Rhes KO male, but not female mice. The results show that Rhes protein plays an important role on MDMA-mediated neuroinflammation and neurodegeneration dependent on gender and age, and confirm the important role of Rhes protein in neuroinflammatory and neurodegenerative processes.

Highlights

Ras homolog enriched in striatum (Rhes) belongs to the Ras superfamily that includes a group of small guanosine triphosphate (GTP)-binding proteins that exert pleiotropic effects on cell function [1]
Starting from results of our research group showing that adult and middle-aged Rhes KO mice develop a spontaneous and age-dependent increase in astroglial and microglial cells, in both STR and substantia nigra pars compacta (SNc), which was more marked in male than in female mice [10], the present study examined the role of Rhes protein on the effects of the psychostimulant drug MDMA on glial fibrillary acidic protein (GFAP) and CD11b and evaluated if its effects were influenced by age and gender
Results show that glial activation in the nigrostriatal and mesocortical systems in response to MDMA administration is increased in Rhes KO adult male mice as compared with WT mice only in selective cases (GFAP in STR and CD11b in SNc), while decrease in tyrosine hydroxylase (TH) in KO mice was observed in most cases

Summary

Introduction

Ras homolog enriched in striatum (Rhes) belongs to the Ras superfamily that includes a group of small guanosine triphosphate (GTP)-binding proteins that exert pleiotropic effects on cell function [1]. A previous study of our laboratory demonstrated that Rhes KO male mice spontaneously develop an age-dependent loss of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNc) and a progressive deficit in motor coordination and balance [7]. Our laboratory investigated the contribution of Rhes to neuroinflammation, demonstrating that lack of Rhes caused an increase of astrogliosis and microgliosis in KO mice [10]. These findings are important since epidemiological and experimental evidence indicate that, among the possible etiopathogenic factors, neuroinflammation is one of major driver for progression of psychiatric disorders such as schizophrenia [11,12,13]. Glial cell activation is a key player in DAergic neuron degeneration, such as in Parkinson’s disease (PD) [14,15,16]

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