Abstract
The vesicular monoamine transporter 2 (VMAT2) has a range of functions in the central nervous system, from sequestering toxins to providing conditions for the quantal release of monoaminergic neurotransmitters. Monoamine signaling regulates diverse functions from arousal to mood, movement, and motivation, and dysregulation of VMAT2 function is implicated in various neuropsychiatric diseases. While all monoamine-releasing neurons express the Vmat2 gene, only a subset is positive for the calcium-binding protein Calbindin 2 (Calb2; aka Calretinin, 29 kDa Calbindin). We recently showed that about half of the dopamine neurons in the mouse midbrain are positive for Calb2 and that Calb2 is an early developmental marker of midbrain dopamine cells. Calb2-positive neurons have also been identified in other monoaminergic areas, yet the role of Calb2-positive monoaminergic neurons is poorly understood. To selectively address the impact of Calb2-positive monoaminergic neurons in behavioral regulation, we took advantage of the Cre-LoxP system to create a new conditional knockout (cKO) mouse line in which Vmat2 expression is deleted selectively in Calb2-Cre-positive neurons. In this Vmat2lox/lox;Calb2−Cre cKO mouse line, gene targeting of Vmat2 was observed in several distinct monoaminergic areas. By comparing control and cKO mice in a series of behavioral tests, specific dissimilarities were identified. In particular, cKO mice were smaller than control mice and showed heightened sensitivity to the stereotypy-inducing effects of amphetamine and slight reductions in preference toward sucrose and ethanol, as well as a blunted response in the elevated plus maze test. These data uncover new knowledge about the role of genetically defined subtypes of neurons in the brain’s monoaminergic systems.
Highlights
The monoamine systems of the brain are crucial for normal brain function and their dysfunction is highly correlated with neuropsychiatric and neurological disorders (Ng et al, 2015)
Following up on data obtained in a microarray analysis of the mouse midbrain, by comparing expression in the ventral tegmental area (VTA) with the substantia nigra pars compacta (SNc) using histological methods we have previously shown that Calbindin 2 (Calb2) mRNA is prominent in both the VTA and the SNc, with the strongest signals detected in lateral VTA, rostral linear nucleus (RLi) and SNc, and somewhat weaker in the medially positioned interfascicular nucleus (IF; Viereckel et al, 2016)
Further following up on the identification of Calb2-positive neurons in the ventral midbrain of the adult mouse, we recently addressed the embryonal development of this same brain area
Summary
The monoamine systems of the brain are crucial for normal brain function and their dysfunction is highly correlated with neuropsychiatric and neurological disorders (Ng et al, 2015). Monoamine signaling is associated with motor regulation (Schultz et al, 1989), arousal (Haas et al, 2008; Sara and Bouret, 2012), emotional behaviors (Cools et al, 2008; Likhtik and Johansen, 2019), learning (Keiflin and Janak, 2015) and motivation (Fields et al, 2007; Cools, 2008; Salamone and Correa, 2012) Following their important roles, compromised monoaminergic function is linked to several neurological and neuropsychiatric diseases such as Parkinson’s Disease, substance use disorder, depression, and schizophrenia, as well as brain dopamineserotonin vesicular transport disease (Christiansen et al, 2007; Gutiérrez et al, 2007; Rilstone et al, 2013; Padmakumar et al, 2019). Drugs such as reserpine and amphetamine that affect monoamine packaging in synaptic vesicles by acting directly on VMAT2 have profound acute and prolonged effects on behavior by influence on both motor and cognitive functions (Schuldiner et al, 1995; Sulzer et al, 2005)
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