Elevated endogenous GDNF induces altered dopamine signalling in mice and correlates with clinical severity in schizophrenia

Abstract

Presynaptic increase in striatal dopamine is the primary dopaminergic abnormality in schizophrenia, but the underlying mechanisms are not understood. Here, we hypothesized that increased expression of endogenous GDNF could induce dopaminergic abnormalities that resemble those seen in schizophrenia. To test the impact of GDNF elevation, without inducing adverse effects caused by ectopic overexpression, we developed a novel in vivo approach to conditionally increase endogenous GDNF expression. We found that a 2–3-fold increase in endogenous GDNF in the brain was sufficient to induce molecular, cellular, and functional changes in dopamine signalling in the striatum and prefrontal cortex, including increased striatal presynaptic dopamine levels and reduction of dopamine in prefrontal cortex. Mechanistically, we identified adenosine A2a receptor (A2AR), a G-protein coupled receptor that modulates dopaminergic signalling, as a possible mediator of GDNF-driven dopaminergic abnormalities. We further showed that pharmacological inhibition of A2AR with istradefylline partially normalised striatal GDNF and striatal and cortical dopamine levels in mice. Lastly, we found that GDNF levels are increased in the cerebrospinal fluid of first episode psychosis patients, and in post-mortem striatum of schizophrenia patients. Our results reveal a possible contributor for increased striatal dopamine signalling in a subgroup of schizophrenia patients and suggest that GDNF—A2AR crosstalk may regulate dopamine function in a therapeutically targetable manner.

Untranslated regions of brain-derived neurotrophic factor mRNA control its translatability and subcellular localization

“…In this study, we use three different in vitro approaches—luciferase assay, translating ribosome affinity purification(TRAP), and de novo protein synthesis assay—to show that the long Bdnf 3′ UTR does not have repressive effects on protein synthesis. Moreover, by in vivo experiments, using a novel conditional 3′UTR replacement approach ( 37 , 38 ), we demonstrate reduced BDNF expression in the brain, indicating that the Bdnf 3′ UTR indeed does not have a repressive effect in this tissue. In contrast, 3′ UTR replacement leads to higher BDNF levels in heart and lungs, suggesting differential 3′UTR–targeted mechanisms of posttranscriptional regulation of Bdnf expression in neuronal and nonneuronal tissues.…”

Increased Physiological GDNF Levels Have No Effect on Dopamine Neuron Protection and Restoration in a Proteasome Inhibition Mouse Model of Parkinson’s Disease

“…Here, we asked whether adult-onset elevation of endogenous GDNF has therapeutic potential in PD treatment. To address this possibility and to bypass the developmental effects of endogenous GDNF overexpression, we used the conditional GDNF hypermorphic (Gdnf cHyper ) mice (Mätlik et al, 2022).…”

“…Bedding material and cages (aspen chips, Tapvei Oy) were changed weekly along with wooden tube and aspen shavings as enrichment. Generation and genotyping of Gdnf-floxed and GDNF conditional hypermorphic (cHyper) mice were described previously (Kopra et al, 2015;Mätlik et al, 2022). A schematic of the Gdnf cHyper allele is shown on…”

“…AAV5-Cre and AAV5-GDNF injections were performed as described previously (Mätlik et al, 2022). Briefly, a 33-G blunt NanoFil needle (World Precision Instruments) was inserted into the brain parenchyma at a 10°angle to avoid damaging the lateral ventricle.…”

“…To that end, we developed GDNF conditional hypermorphic (Gdnf cHyper ) mice (Mätlik et al, 2022). We analyzed the therapeutic potential of endogenous GDNF upregulation in the striatum in the LC-induced model of PD, using both neuroprotection and neurorestoration paradigms.…”