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

Mätlik, Kärt ; Garton, Daniel R. ; Montaño-Rodríguez, Ana R. ; Olfat, Soophie ; Eren, Feride ; Casserly, Laoise ; Damdimopoulos, Anastasios ; Panhelainen, Anne ; Porokuokka, L. Lauriina and Kopra, Jaakko J. , et al. (2022) In Molecular Psychiatry 27(8). p.3247-3261
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Psychiatry
volume
27
issue
8
pages
3247 - 3261
publisher
Nature Publishing Group
external identifiers
  • pmid:35618883
  • scopus:85130751563
ISSN
1359-4184
DOI
10.1038/s41380-022-01554-2
language
English
LU publication?
yes
id
4ea25fd6-4843-4f08-b042-4a52b8c1956e
date added to LUP
2022-10-10 11:46:47
date last changed
2024-04-18 08:28:33
@article{4ea25fd6-4843-4f08-b042-4a52b8c1956e,
  abstract     = {{<p>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 (A<sub>2A</sub>R), 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 A<sub>2A</sub>R 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—A<sub>2A</sub>R crosstalk may regulate dopamine function in a therapeutically targetable manner.</p>}},
  author       = {{Mätlik, Kärt and Garton, Daniel R. and Montaño-Rodríguez, Ana R. and Olfat, Soophie and Eren, Feride and Casserly, Laoise and Damdimopoulos, Anastasios and Panhelainen, Anne and Porokuokka, L. Lauriina and Kopra, Jaakko J. and Turconi, Giorgio and Schweizer, Nadine and Bereczki, Erika and Piehl, Fredrik and Engberg, Göran and Cervenka, Simon and Piepponen, T. Petteri and Zhang, Fu Ping and Sipilä, Petra and Jakobsson, Johan and Sellgren, Carl M. and Erhardt, Sophie and Andressoo, Jaan Olle}},
  issn         = {{1359-4184}},
  language     = {{eng}},
  number       = {{8}},
  pages        = {{3247--3261}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Molecular Psychiatry}},
  title        = {{Elevated endogenous GDNF induces altered dopamine signalling in mice and correlates with clinical severity in schizophrenia}},
  url          = {{http://dx.doi.org/10.1038/s41380-022-01554-2}},
  doi          = {{10.1038/s41380-022-01554-2}},
  volume       = {{27}},
  year         = {{2022}},
}