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

Abstract

The lateral habenula (LHb), a key regulator of monoaminergic brain regions, is activated by negatively-valenced events. Its hyperactivity is associated with depression. While enhanced excitatory input to the LHb has been linked to depression, little is known about inhibitory transmission. We discovered that 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 towards 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 remarkable form of transmission may be important for determining the impact of negative life events on mood and behavior.

Single-neuron identification of chemical constituents, physiological changes, and metabolism using mass spectrometry

“…Recently, a growing number of studies using a combination of electrophysiological, immunohistochemical, and optogenetic techniques have shown that Glu and GABA may coexist and be coreleased from a single-neuron terminal (42)(43)(44). Our findings provided supporting evidence of the coexistence of Glu and GABA in the soma of all neuron types (both excitatory and inhibitory).…”

Lateral Hypothalamic Area Glutamatergic Neurons and Their Projections to the Lateral Habenula Regulate Feeding and Reward

“…We found that the LHA sends a strong projection to the LHb, an area involved in promoting aversion and negatively regulating reward-related behaviors. Previous data has demonstrated a similar aversive phenotype when activating LHb inputs from the entopenduncular nucleus, an output of the basal ganglia that is located lateral to the LHA (Shabel et al, 2012). It is important to note that the entopenduncular nucleus and lateral hypothalamic area are neighboring structures and it is possible that viral targeting of one region could result in viral transduction of the neighboring region.…”

“…However, the entopenduncular nucleus, and the globus pallidus internus (the primate homolog) contains mainly GABAergic neurons (Oertel et al, 1984;Stephenson et al, 2005). However, it was recently shown that some entopenduncular projections to the LHb can switch from using GABA to glutamate under certain conditions (Shabel et al, 2014). In addition, our method for targeting the LHA glutamatergic neurons, using cre-inducible ChR2 and medial injection sites, did not result in substantial infection of entopenduncular neurons (Fig.…”

“…Following retrobead injections into the LHb, we observed LHb-projecting neurons in both the entopenduncular nucleus and the LHA. However, the entopenduncular nucleus, and the globus pallidus internus (the primate homolog) contains mainly GABAergic neurons (Oertel et al, 1984;Stephenson et al, 2005). However, it was recently shown that some entopenduncular projections to the LHb can switch from using GABA to glutamate under certain conditions (Shabel et al, 2014).…”

Altered Microbiota Composition Mediates Depressive Behavior During Chronic Stress

“…Evidence is now accumulating that the habenula is acting as a "disappointment" center of the brain, with neurons in this region being excited in the absence of reward and inhibited in rewarding situations [66][67][68][69] . Animal models displaying depressive behavior also show increased activation of lateral habenular neurons, in turn feeding to excite the VTA [70][71][72] . Moreover, experiments involving deep brain stimulation of the habenula in both rats and humans were able to reduce neuronal activity and improve depressive symptoms 69,70 .…”