Genetic deletion of vesicular glutamate transporter in dopamine neurons increases vulnerability to MPTP-induced neurotoxicity in mice.

A subset of midbrain dopamine (DA) neurons express vesicular glutamate transporter 2 (VgluT2), which facilitates synaptic vesicle loading of glutamate. Recent studies indicate that such expression can modulate DA-dependent reward behaviors, but little is known about functional consequences of DA neuron VgluT2 expression in neurodegenerative diseases like Parkinson's disease (PD). Here, we report that selective deletion of VgluT2 in DA neurons in conditional VgluT2-KO (VgluT2-cKO) mice abolished glutamate release from DA neurons, reduced their expression of brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB), and exacerbated the pathological effects of exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, viral rescue of VgluT2 expression in DA neurons of VglutT2-cKO mice restored BDNF/TrkB expression and attenuated MPTP-induced DA neuron loss and locomotor impairment. Together, these findings indicate that VgluT2 expression in DA neurons is neuroprotective. Genetic or environmental factors causing reduced expression or function of VgluT2 in DA neurons may place some individuals at increased risk for DA neuron degeneration. Therefore, maintaining physiological expression and function of VgluT2 in DA neurons may represent a valid molecular target for the development of preventive therapeutic interventions for PD.

Neural circuits and nicotinic acetylcholine receptors mediate the cholinergic regulation of midbrain dopaminergic neurons and nicotine dependence.

Midbrain dopaminergic (DA) neurons are governed by an endogenous cholinergic system, originated in the mesopontine nuclei. Nicotine hijacks nicotinic acetylcholine receptors (nAChRs) and interferes with physiological function of the cholinergic system. In this review, we describe the anatomical organization of the cholinergic system and the key nAChR subtypes mediating cholinergic regulation of DA transmission and nicotine reward and dependence, in an effort to identify potential targets for smoking intervention. Cholinergic modulation of midbrain DA systems relies on topographic organization of mesopontine cholinergic projections, and activation of nAChRs in midbrain DA neurons. Previous studies have revealed that α4, α6, and ß2 subunit-containing nAChRs expressed in midbrain DA neurons and their terminals in the striatum regulate firings of midbrain DA neurons and activity-dependent dopamine release in the striatum. These nAChRs undergo modification upon chronic nicotine exposure. Clinical investigation has demonstrated that partial agonists of these receptors elevate the success rate of smoking cessation relative to placebo. However, further investigations are required to refine the drug targets to mitigate unpleasant side-effects.

Impaired motor coordination in Pitx3 overexpression mice.

Midbrain dopaminergic (DA) neurons are involved in the regulation of voluntary movement and in emotion-related behaviors and are affected in Parkinson's disease (PD). The homeodomain transcription factor Pitx3, which is uniquely expressed in midbrain DA neurons, plays a critical role in the development, function and maintenance of midbrain DA neurons. Pitx3 deficiency results in selective deficits of midbrain DA neurons in the substantia nigra pars compacta (SNc), reminiscent of the specific DA neuronal loss observed in PD. In this study, we found that selective overexpression of Pitx3 in intact midbrain DA neurons significantly affects the function of midbrain DA neurons. We observed changes in DA levels and gene expressions in mice overexpressing Pitx3. Furthermore, motor coordination and locomotion activities are significantly affected in mice overexpressing Pitx3, suggesting that the expression level of Pitx3 plays an important role in the function of midbrain DA neuron in vivo.