An essential role of acetylcholine-glutamate synergy at habenular synapses in nicotine dependence.

Silke Frahm,Gudrun Ahnert-Hilger,Johannes-Friedrich Zander,Ines Ibañez-Tallon,Beatriz Antolin-Fontes,Andreas Görlich

doi:10.7554/elife.11396

Silke Frahm, Gudrun Ahnert-Hilger + Show 4 more

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A great deal of interest has been focused recently on the habenula and its critical role in aversion, negative-reward and drug dependence. Using a conditional mouse model of the ACh-synthesizing enzyme choline acetyltransferase (Chat), we report that local elimination of acetylcholine (ACh) in medial habenula (MHb) neurons alters glutamate corelease and presynaptic facilitation. Electron microscopy and immuno-isolation analyses revealed colocalization of ACh and glutamate vesicular transporters in synaptic vesicles (SVs) in the central IPN. Glutamate reuptake in SVs prepared from the IPN was increased by ACh, indicating vesicular synergy. Mice lacking CHAT in habenular neurons were insensitive to nicotine-conditioned reward and withdrawal. These data demonstrate that ACh controls the quantal size and release frequency of glutamate at habenular synapses, and suggest that the synergistic functions of ACh and glutamate may be generally important for modulation of cholinergic circuit function and behavior.

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Acetylcholine (ACh) was first described in the heart muscle (Loewi, 1921), and later in the peripheral nervous system, as a fast acting neurotransmitter at the neuromuscular junction (Bennett, 2000)
choline acetyltransferase (CHAT) is the only enzyme that synthesizes ACh, and it is expressed at the neuromuscular junction and in several brain areas including the medial habenula (MHb), basal forebrain (BF), laterodorsal tegmental nucleus (LDTg), third cranial nerve (3N) and nucleus of the solitary tract (NTS) (Figure 1A)
Double immunostaining with CHAT and EYFP antibodies in Kiaa1107-Cre mice crossed to reporter Gt(ROSA)26Sortm1(EYFP)Cos mice (Figure 1D) demonstrated that 99% (1912 of 1933) of CHAT positive neurons in the MHb are positive for the EYFP reporter

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Acetylcholine (ACh) was first described in the heart muscle (Loewi, 1921), and later in the peripheral nervous system, as a fast acting neurotransmitter at the neuromuscular junction (Bennett, 2000). At synapses with a high concentration of AChE, ACh is so quickly degraded that a single molecule cannot activate a second receptor (Kuffler and Yoshikami, 1975). Since both nicotinic (nAChRs) and muscarinic (mAChRs) acetylcholine receptors are often localized extrasynaptically on dendrites and somata, and presynaptically at axonal terminals (De-Miguel and Fuxe, 2012; Descarries et al, 1997; Role and Berg, 1996), it is thought that ACh volume transmission in the IPN requires high frequency stimulation of habenular neurons (Ren et al, 2011). The release of ACh from habenular terminals is consistent with genetic studies demonstrating altered responses to nicotine addiction as a consequence of mutations in nicotinic receptors that are enriched in the MHbIPN (Antolin-Fontes et al, 2015; Fowler et al, 2011; Jackson et al, 2010; Salas et al, 2009)

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