Abstract
Motivated reward-seeking behaviours are governed by dopaminergic ventral tegmental area projections to the nucleus accumbens. In addition to dopamine, these mesoaccumbal terminals co-release other neurotransmitters including glutamate and GABA, whose roles in regulating motivated behaviours are currently being investigated. Here we demonstrate that loss of the E3-ubiquitin ligase, UBE3A, from tyrosine hydroxylase-expressing neurons impairs mesoaccumbal, non-canonical GABA co-release and enhances reward-seeking behaviour measured by optical self-stimulation.
Highlights
We serendipitously discovered that the loss of the E3-ubiquitin ligase, Ube3a, did not directly alter ventral tegmental area (VTA)-to-nucleus accumbens (NAc) dopamine release but is essential for gamma-aminobutyric acid (GABA) co-release and the modulation of positively reinforced behaviour
We used a 30 Hz optical-stimulation paradigm, as this stimulation frequency is within a range previously shown to produce robust DA release at NAc terminals, and has been used across various behavioural paradigms examining the effects of neuromodulatory release in vivo[10,11,12,13,14]
Using an optical-stimulation paradigm similar to that used in the behavioural experiments, we found that THCRE::Ube3aFLOX/p þ mice exhibit diminished GABAergic currents at 30 Hz stimulation of VTA-to-NAc terminals compared with control mice (Fig. 4h)
Summary
Mesoaccumbal optical stimulation in a Ube3a-null model. In an effort originally designed to elucidate mechanisms underlying dopaminergic dysfunction in an Angelman syndrome mouse model[9], we used a reductionist approach to selectively manipulate the mesoaccumbal dopaminergic pathway. Similar to previous electrophysiological studies[15] and our own anatomical evidence showing that the vast majority of ChR2-expressing neurons in the VTA are TH þ (Supplementary Fig. 4a,b), we found that reserpine abolished most optically evoked GABAergic currents in the NAc (Supplementary Fig. 4c) This further demonstrates that our optical stimulation almost exclusively evoked GABA release from dopaminergic terminals. Exogenous expression of VGAT within TH þ terminals was sufficient to normalize optical intracranial selfstimulation responding in THCRE::Ube3aFLOX/p þ ::DIO-VGAT mice compared with THCRE::Ube3am þ /p þ ::DIO-VGAT mice (Fig. 5e,f), suggesting a causal relationship between the observed deficits in GABA co-release and alterations in motivational drive in the absence of UBE3A (Fig. 5f, P40.05)
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