GABA/glutamate co-release controls habenula output and is modified by antidepressant treatment

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Science  19 Sep 2014:
Vol. 345, Issue 6203, pp. 1494-1498
DOI: 10.1126/science.1250469

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A pathway that controls our mood

A brain area called the lateral habenula is involved in negative motivation and may thus play a role in depression. Shabel et al. investigated synaptic transmission in a brain pathway to the lateral habenula that transmits disappointment signals. Surprisingly, they found the simultaneous release of two antagonistic substances, glutamate and GABA, from individual nerve cells. In an animal model of depression, GABA release was reduced in this pathway. A widely used antidepressant drug, however, increased GABA co-release. These results reveal an unusual synaptic mechanism that affects lateral habenula activity. This mechanism may be instrumental for regulating the emotional impact of disappointment.

Science, this issue p. 1494


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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