Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

A new collaborative study from the Oxford Parkinson’s Disease Centre led by Prof Stephanie Cragg and Dr Bradley Roberts has revealed that GABA transporters on astrocytes, the brain's lesser known yet critically important cells, support dopamine release and are sites of early dysfunction in parkinsonism.

Striatal immunofluorescence signals for astrocyte marker S100β and neuronal marker NeuN
Striatal immunofluorescence signals for astrocyte marker S100β (magenta) and neuronal marker NeuN (yellow)

The release of the neurotransmitter dopamine in the brain region called the striatum plays key roles in both our motivation and how we select our actions. This release is dysregulated across diverse disorders including Parkinson's and various addictions. Unravelling the mechanisms by which dopamine release in the striatum is governed, and understanding how these mechanisms might be dysfunctional in disease, is critical for identifying novel targets for disease-modifying therapies.

A new study funded by Parkinson's UK and published in Nature Communications led by Professor Stephanie Cragg and Dr Bradley Roberts, and in collaboration with the Oxford Parkinson’s Disease Centre, uncovers new observations about how non-neuronal cells in the brain, namely astrocytes, regulate striatal dopamine release and are sites of early dysfunction in Parkinson’s.

Astrocytes are thought to outnumber neurons in the brain, but our understanding of how astrocytes act within brain circuits lags significantly behind our understanding of neurons. In their new paper, the team reveal that astrocytes critically support striatal dopamine release through the uptake of extracellular GABA via astrocytic GABA uptake transporters, thereby limiting the tonic inhibition by GABA on striatal dopamine release. In a mouse model of early parkinsonism, the team observed that astrocytic GABA transporter function was downregulated and tonic inhibition of dopamine release by extracellular GABA augmented, leading to diminished striatal dopamine output. The study also makes the novel finding that, in addition to reduced striatal dopamine release in early parkinsonism, GABA co-release from dopamine axons in striatum is also reduced.

Dr Roberts said: "These findings are exciting as they uncover striatal GABA transporters and astrocytes, for the first time, as novel loci for governing dopamine output in striatum as well as sites of early dysfunction in Parkinson’s disease. These findings add to the recent growing body of literature implicating astrocytes and their transporters as sites of early dysfunction across neurodegenerative diseases, and could provide novel therapeutic targets for Parkinson’s disease."

Dr Beckie Port, Research Manager at Parkinson's UK said: “Identifying areas of the brain where the problems in Parkinson’s start, earlier, is a big step towards developing effective treatment. Armed with this knowledge, we are on our way to identifying specific targets within the brain and developing the next generation of treatments that can stop Parkinson’s in its tracks - something no current treatment can do. Parkinson’s UK is excited to be part of this promising research.”

Full text description is subtitled directly below image in the relevant news article.

Image description: Under normal circumstances (control group), GABA released from GABAergic striatal neurons can spillover to act at GABA receptors on dopamine axons, inhibiting dopamine and GABA co-release. The level of GABA spillover and tonic inhibition of dopamine release is determined by the activity of GABA transporters (GATs) located on astrocytes, which remove GABA from the extracellular space. In a mouse model of early parkinsonism, striatal GAT expression is downregulated, resulting in augmented tonic inhibition of dopamine release by GABA. Co-release of GABA from dopamine axons is also reduced.  

 

The full publication “GABA uptake transporters support dopamine release in dorsal striatum with maladaptive downregulation in a parkinsonism model” is available to read in Nature Communications.

Similar stories

Can humans hibernate?

Illuminating new TEDx Talk from Professor of Sleep Physiology Vladyslav Vyazovskiy

Annie Park to advance our understanding of how the brain encodes reward with new Wellcome Trust Award

Congratulations are in order for Postdoctoral Fellow Dr Annie Park who has been awarded a prestigious Wellcome Early-Career Award.

New insights into chemogenetic designer drugs to enhance our study of behaviour

A collaborative team of researchers in DPAG and Pharmacology led by Dr Lukas Krone have uncovered striking new data demonstrating that two widely used designer drugs used to turn populations of neurons on and off in the brain cause unexpected effects on sleep. These results demonstrate a critical need to improve chemogenetic approaches in behavioural studies.

Unlocking the Secrets of cAMP Signalling in the Heart: A Pathway to Targeted Therapeutics

A new Zaccolo group study has revealed key new insights into the role of cAMP signalling in both healthy and disease settings within the heart. They have identified new cAMP nanodomains in cardiac muscle cells that have far reaching implications for the treatment of heart disease.

Key exosome subtype in cancer progression identified

Collaborative work from DPAG and Oncology researchers has revealed a potential new pathway to block the production of a specific group of exosomes made in the cell’s recycling system that can promote the growth of cancerous tumours.