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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Parvalbumin‐positive interneurons (PV+) are a key component of inhibitory networks in the brain and are known to modulate memory and learning by shaping network activity. The mechanisms of PV+ neuron generation and maintenance are not fully understood, yet current evidence suggests that signalling via the glial cell line‐derived neurotrophic factor (GDNF) receptor GFRα1 positively modulates the migration and differentiation of PV+ interneurons in the cortex. Whether GDNF also regulates PV+ cells in the hippocampus is currently unknown. In this study, we utilized a Gdnf “hypermorph” mouse model where GDNF is overexpressed from the native gene locus, providing greatly increased spatial and temporal specificity of protein expression over established models of ectopic expression. Gdnfwt/hyper mice demonstrated impairments in long‐term memory performance in the Morris water maze test and an increase in inhibitory tone in the hippocampus measured electrophysiologically in acute brain slice preparations. Increased PV+ cell number was confirmed immunohistochemically in the hippocampus and in discrete cortical areas and an increase in epileptic seizure threshold was observed in vivo. The data consolidate prior evidence for the actions of GDNF as a regulator of PV+ cell development in the cortex and demonstrate functional effects upon network excitability via modulation of functional GABAergic signalling and under epileptic challenge.

Parkinson’s disease (PD) is a progressive neurodegenerative disease that comprises a range of motor and non-motor symptoms. Glial cell line-derived neurotrophic factor (GDNF) promotes the survival of dopamine neuronsin vitroandin vivo, and intracranial delivery of GDNF has been tested in six clinical trials for treating PD. However, clinical trials with ectopic GDNF have yielded variable results, which could in part result from abnormal expression site and levels caused by ectopic overexpression. Therefore, an important open question is whether an increase in endogenous GDNF expression could be potent in reversing PD progression. Here, we tested the therapeutic potential of endogenous GDNF using mice in which endogenous GDNF can be conditionally upregulated specifically in cells that express GDNF naturally (conditional GDNF hypermorphic mice;GdnfcHyper). We analyzed the impact of endogenous GDNF upregulation in both neuroprotection and neurorestoration procedures, and for both motor and non-motor symptoms in the proteasome inhibitor lactacystin (LC) model of PD. Our results showed that upregulation of endogenous GDNF in the adult striatum is not protective in LC-induced PD model in mice. Since age is the largest risk factor for PD, we also analyzed the effect of deletion of endogenous GDNF in agedGdnfconditional knock-out mice. We found that GDNF deletion does not increase susceptibility to LC-induced damage. We conclude that endogenous GDNF does not impact the outcome in the LC-induced proteasome inhibition mouse model of Parkinson’s disease.Significance StatementGlial cell line-derived neurotrophic factor GDNF is a strong enhancer of dopamine neuron function and survival. Ectopic delivery of GDNF has been tested in six clinical trials to treat Parkinson’s disease with promising but inconclusive results. Whether an increase in endogenous GDNF expression could be more beneficial in protecting or restoring damaged dopamine neurons than ectopic GDNF delivery has remained unknown. Here, we use GDNF conditional hypermorph and GDNF conditional knock-out mice to study the role of endogenous GDNF in a mouse model of Parkinson’s disease. Our findings demonstrate that neither an increase or loss of endogenous GDNF expression impacts dopamine neuron survival and recovery in proteasome inhibition model of Parkinson’s disease.

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