Increased Endogenous GDNF in Mice Protects Against Age-Related Decline in Neuronal Cholinergic Markers.

Sumonto Mitra,Taher Darreh-Shori,Matilde Aquilino,Jaan-Olle Andressoo,Kärt Mätlik,Giorgio Turconi,Maria Eriksdotter

doi:10.3389/fnagi.2021.714186

Abstract

Gradual decline in cholinergic transmission and cognitive function occurs during normal aging, whereas pathological loss of cholinergic function is a hallmark of different types of dementia, including Alzheimer’s disease (AD), Lewy body dementia (LBD), and Parkinson’s disease dementia (PDD). Glial cell line-derived neurotrophic factor (GDNF) is known to modulate and enhance the dopamine system. However, how endogenous GDNF influences brain cholinergic transmission has remained elusive. In this study, we explored the effect of a twofold increase in endogenous GDNF (Gdnf hypermorphic mice, Gdnfwt/hyper) on cholinergic markers and cognitive function upon aging. We found that Gdnfwt/hyper mice resisted an overall age-associated decline in the cholinergic index observed in the brain of Gdnfwt/wt animals. Biochemical analysis revealed that the level of nerve growth factor (NGF), which is important for survival and function of central cholinergic neurons, was significantly increased in several brain areas of old Gdnfwt/hyper mice. Analysis of expression of genes involved in cholinergic transmission in the cortex and striatum confirmed modulation of cholinergic pathways by GDNF upon aging. In line with these findings, Gdnfwt/hyper mice did not undergo an age-related decline in cognitive function in the Y-maze test, as observed in the wild type littermates. Our results identify endogenous GDNF as a potential modulator of cholinergic transmission and call for future studies on endogenous GDNF function in neurodegenerative disorders characterized by cognitive impairments, including AD, LBD, and PDD.

Highlights

Glial cell line-derived neurotrophic factor (GDNF) is a secretory protein which protects dopaminergic neurons in vitro and in vivo (Lin et al, 1993; Hoffer et al, 1994)
Our results suggest that GDNF may influence cholinergic transmission by regulating activity of key components and regulators of the cholinergic machinery, including ACh-biosynthesizing enzyme choline acetyltransferase (ChAT), the high affinity choline transporter (ChT) and nerve growth factor (NGF), respectively
This effect seems to be significant to the cholinergic system in the cortex, which plays a key role in cognition (Miller, 2000) and it is mostly affected in several conditions associated with dementia, including Alzheimer’s disease (AD), Parkinson’s disease dementia (PDD), and Lewy body dementia (LBD) (Francis and Perry, 2007; Dickerson et al, 2009)

Summary

Introduction

Glial cell line-derived neurotrophic factor (GDNF) is a secretory protein which protects dopaminergic neurons in vitro and in vivo (Lin et al, 1993; Hoffer et al, 1994). GDNF application potentiates striatal dopaminergic fiber outgrowth and elevates striatal dopamine levels The striatal dopaminergic signaling is regulated by striatal cholinergic interneurons (Cachope and Cheer, 2014; Sulzer et al, 2016), which primarily control reward and addiction related behaviors (Berlanga et al, 2003; Gonzales and Smith, 2015; Stouffer et al, 2015), but can influence cognition (Ztaou et al, 2018; Galaj et al, 2019), social behavior (Martos et al, 2017), behavioral flexibility (Ragozzino et al, 2002, 2009; McCool et al, 2008) and motor function (Pisani et al, 2007)

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Results

Conclusion