Abstract
The maintenance of excitatory and inhibitory balance in the brain is essential for its function. Here we find that the developmental axon guidance receptor Roundabout 2 (Robo2) is critical for the maintenance of inhibitory synapses in the adult ventral tegmental area (VTA), a brain region important for the production of the neurotransmitter dopamine. Following selective genetic inactivation of Robo2 in the adult VTA of mice, reduced inhibitory control results in altered neural activity patterns, enhanced phasic dopamine release, behavioral hyperactivity, associative learning deficits, and a paradoxical inversion of psychostimulant responses. These behavioral phenotypes could be phenocopied by selective inactivation of synaptic transmission from local GABAergic neurons of the VTA, demonstrating an important function for Robo2 in regulating the excitatory and inhibitory balance of the adult brain.
Highlights
The midbrain dopamine system, consisting of the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc), is essential for motor function, motivation, reward, learning, and memory
To confirm the expression of Roundabout 2 (Robo2) in the VTA, we performed immunostaining for Robo2 and tyrosine hydroxylase (TH, a dopamine neuron marker) on brain sections from adult mice (>8 weeks old)
Robo2 expression was observed throughout the VTA, largely localized to TH-positive neurons, though several TH-negative neurons were observed to express Robo2 (TH+Robo2+ = 75.28 ± 0.56%, TH+Robo2À = 7.81 ± 1.46%, and TH-Robo2+ = 16.90 ± 1.77%, n = 4) (Figure 1A)
Summary
The midbrain dopamine system, consisting of the VTA and substantia nigra pars compacta (SNc), is essential for motor function, motivation, reward, learning, and memory. Alterations in the activity patterns of dopamine neurons have been proposed as a key contributor to mental illness (Grace, 1991). In addition to dopamine, accumulating evidence points to an essential balance of excitatory and inhibitory neurotransmitter systems in the brain to allow for proper function. Shifts in this balance are increasingly linked to a variety of mental disorders including schizophrenia (Eichler and Meier, 2008) and autism (Nelson and Valakh, 2015). The VTA dopamine system is broadly implicated in addiction where changes in inhibitory and excitatory strength are proposed to underlie drug-seeking behavior (Chen et al, 2010). The cellular mechanisms that maintain the excitatory and inhibitory synaptic control of the adult VTA are not well known, but resolving these processes has important implications for resolving the molecular regulation of circuit connectivity
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