GABA/glutamate co-release controls habenula output and is modified by antidepressant treatment
Open accessAbstract
The lateral habenula (LHb), a key regulator of monoaminergic brain regions, is activated by negatively valenced events. Its hyperactivity is associated with depression. Although enhanced excitatory input to the LHb has been linked to depression, little is known about inhibitory transmission. We discovered that γ-aminobutyric acid (GABA) is co-released with its functional opponent, glutamate, from long-range basal ganglia inputs (which signal negative events) to limit LHb activity in rodents. At this synapse, the balance of GABA/glutamate signaling is shifted toward reduced GABA in a model of depression and increased GABA by antidepressant treatment. GABA and glutamate co-release therefore controls LHb activity, and regulation of this form of transmission may be important for determining the effect of negative life events on mood and behavior.
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The excitatory/inhibitory ratio at each synapse can be adjusted independently by regulating vesicular transporter activity or postsynaptic receptor composition.
“The excitatory/ inhibitory ratio at each synapse can be adjusted independently by regulating the activity of the vesicular transporters 26,41 or adjusting the composition of postsynaptic receptors.”
From Synaptic and circuit functions of multitransmitter neurons in the mammalian brain (2023) · cites this paper as [26]
LHb-projecting EP/GPi neurons were later found to transmit both glutamate and GABA and to be capable of exciting and inhibiting LHb neurons.
“Later, they were found to simultaneously transmit both glutamate and GABA and to be capable of both exciting and inhibiting LHb neurons 40,26 (Figure 1A).”
From Synaptic and circuit functions of multitransmitter neurons in the mammalian brain (2023) · cites this paper as [26]
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- Authors
- Shabel, S. J., Proulx, C. D., Piriz, J., & Malinow, R.
- Affiliations
- University of California San Diego (US)
- Grupo de Neurociencia de Sistemas, Instituto de Fisiología y Biofísica Houssay (CONICET-UBA), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
- Corresponding author
- Shabel, Steven J.
- Venue
- Science
- Published
- 2014-09-19
- Volume
- 345
- Issue
- 6203
- Pages
- 1494-1498
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4305433
- OpenAlex
- W2046270739
- Cited by
- 369
- References
- 44
- Citations by year
- 2026: 25 · 2025: 23 · 2024: 24 · 2023: 28 · 2022: 43 · 2021: 29 · 2020: 23 · 2019: 28 · 2018: 41 · 2017: 34 · 2016: 37 · 2015: 28 · 2014: 5
- FWCI
- 15.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Conicet (submittedVersion, cc-by-nc-sa)
- Funders
- National Institute of Mental Health (R01MH091119)
- National Institute of Neurological Disorders and Stroke (NS047101, P30NS047101)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- lateral habenula, glutamate co-release, synaptic inhibition, depression, antidepressant treatment
- MeSH terms
- Channelrhodopsins, Animals, Antidepressive Agents, Depression, gamma-Aminobutyric Acid, Glutamate Decarboxylase, Male, Mice, Inbred C57BL, Synaptic Transmission, Neurons, Rats, Sprague-Dawley, Glutamic Acid, Habenula, Entopeduncular Nucleus, Vesicular Glutamate Transport Protein 2, Mice, Rats
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