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Elevated endogenous GDNF levels associate with schizophrenia in humans and mice

ABSTRACT: Recent studies have identified presynaptic increase in striatal dopamine as the primary dopaminergic abnormality in schizophrenia, responsible for changes in cortical dopamine function in schizophrenic individuals. However, increased dopamine synthesis and release are not recapitulated in existing mouse models, limiting studies on disease progression and potential treatments. We found that the levels of glial cell line-derived neurotrophic factor (GDNF), a strong dopamine system modulator, are increased in the cerebrospinal fluid of first episode psychosis patients. Using a novel strategy to conditionally increase endogenous gene expression, we developed a mouse model with timed elevation of endogenous GDNF. Conditional ‘Knock Up’ of endogenous GDNF expression (GDNF cKU) in the central nervous system at midgestation resulted in an increase of dopamine levels in the presynaptic compartment of nigrostriatal dopamine neurons, hypodopaminergia in the prefrontal cortex (PFC) and schizophrenia-like behavioural deficits in the mouse. RNA sequencing from the PFC revealed gene expression changes similar to those previously found in schizophrenia patients, including downregulation of dopamine receptor 2 and adenosine A2a receptor (A2AR). Treatment of mice with A2AR antagonist istradefylline partially restored striatal and cortical dopamine levels, suggesting a potential therapeutic strategy to alleviate symptoms associated with schizophrenia. Taken together, our results demonstrate that timed increase in GDNF expression is sufficient to drive schizophrenia-like molecular and behavioural phenotypes, and represents a novel model for studying schizophrenia-associated pathologies in mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE162974 | GEO | 2023/01/03

REPOSITORIES: GEO

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Project description:Yapo2017 - A2AR/cAMP/PKA signalling in D2 dopamine receptor expressing medium-spiny neurons This model is described in the article: Detection of phasic dopamine by D1 and D2 striatal medium spiny neurons. Yapo C, Nair AG, Clement L, Castro LR, Hellgren Kotaleski J, Vincent P. J. Physiol. (Lond.) 2017 Aug; : Abstract: The phasic release of dopamine in the striatum determines various aspects of reward and action selection, but the dynamics of dopamine effect on intracellular signalling remains poorly understood. We used genetically-encoded FRET biosensors in striatal brain slices to quantify the effect of transient dopamine on cAMP or PKA-dependent phosphorylation level, and computational modelling to further explore the dynamics of this signalling pathway. Medium-sized spiny neurons (MSNs), which express either D1 or D2 dopamine receptors, responded to dopamine by an increase or a decrease in cAMP, respectively. Transient dopamine showed similar sub-micromolar efficacies on cAMP in both D1 and D2 MSNs, thus challenging the commonly accepted notion that dopamine efficacy is much higher on D2 than on D1 receptors. However, in D2 MSNs, the large decrease in cAMP level triggered by transient dopamine did not translate in a decrease in PKA-dependent phosphorylation level, owing to the efficient inhibition of Protein Phosphatase 1 by DARPP-32. Simulations further suggested that D2 MSNs can also operate in a "tone-sensing" mode, allowing them to detect transient dips in basal dopamine. Overall, our results show that D2 MSNs may sense much more complex patterns of dopamine than previously thought. This article is protected by copyright. All rights reserved. This model is hosted on BioModels Database and identified by: MODEL1701170001. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Elevated endogenous GDNF levels associate with schizophrenia in humans and mice

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