Abstract
The role of changes in dopamine neuronal activity during the development of symptoms in affective disorders remains controversial. Here, we show that inactivation of NMDA receptors on dopaminergic neurons in adult mice led to the development of affective disorder-like symptoms. The loss of NMDA receptors altered activity and caused complete NMDA-insensitivity in dopamine-like neurons. Mutant mice exhibited increased immobility in the forced swim test and a decrease in social interactions. Mutation also led to reduced saccharin intake, however the preference of sweet taste was not significantly decreased. Additionally, we found that while mutant mice were slower to learn instrumental tasks, they were able to reach the same performance levels, had normal sensitivity to feedback and showed similar motivation to exert effort as control animals. Taken together these results show that inducing the loss of NMDA receptor-dependent activity in dopamine neurons is associated with development of affective disorder-like symptoms.
Highlights
We found a significant effect of the mutation on the number of visits to the corners (Supplementary Figure S6d; significant effects in three-way repeated measures analysis of variance (ANOVA), genotype, F1,14 = 7.304, p = 0.0172, difficulty, F6,84 = 32.661, p < 0.0001; drink, F1,98 = 87.102, p < 0.0001, difficulty x drink, F6,98 = 6.939, p < 0.0001) and the number of licks that were performed on the saccharin bottles (Fig. 4e; significant effects in three-way repeated measures ANOVA, genotype, F1,14 = 32.1, p < 0.0001; difficulty, F6,84 = 39.188, p < 0.0001; drink, F1,98 = 40.694, p < 0.0001; difficulty x drink, F6,98 = 29.378, p < 0.0001; genotype x drink, F1,98 = 4.244, p = 0.042) but not on saccharin preference
We found that when the loss of the NR1 subunit was induced in DA neurons in adult mice, there were alterations in the pattern of electrical activity that led to changes in selected behaviours known to be associated with affective disorder symptoms
The fact that the ability to generate doublets was preserved in small fraction of DA neurons in mutant mice indicates that firing two-spike bursts relies on mechanisms that are independent of NMDA receptors
Summary
In mice with halorhodopsin-mediated inhibition of dopamine neuronal activity resulted in behavioural despair-like immobility in forced swim test, decreased sucrose preference[18] and reduced social interactions[19]. In contrast in the mutant mice, NMDA did not change or affect the pattern of activity of DA-like neurons (Fig. 2a and b; Supplementary Tables S4 and S5).
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