GluA3-deficiency in mice is associated with increased social and aggressive behavior and elevated dopamine in striatum

Abstract

Glutamate signaling has been implicated in the regulation of social behavior. AMPA-glutamate receptors are assembled from four subunits (GluA1-4) of mainly GluA1/2 and GluA2/3 tetramers that form ion channels of distinct functional properties. Mice lacking GluA1 showed a reduced anxiety and male aggression. To understand the role of GluA3 in modulating social behavior, we investigated GluA3-deficient mice (Gria3-/Y) on C57BL/6J background. Compared to wild type (WT) littermates (n=14), Gria3-/Y mice (n=13) showed an increase in isolation-induced male aggression (p=0.011) in home cage resident-intruder test; an increase in sociability (p=0.01), and increase in male-male social interactions in neutral arena (p=0.005); an increase in peripheral activities in open field test (p=0.037) with normal anxiety levels in elevated plus maze and light-dark box; and minor deficits in motor and balance function in accelerating rotarod test (p=0.016) with normal grip strength. Gria3-/Y mice showed no significant deficit in spatial memory function in Morris-water maze and Y-maze tests, and normal levels of testosterone. Increased dopamine concentrations in stratum (p=0.034) and reduced serotonin turnover in olfactory bulb (p=0.002) were documented in Gria3-/Y mice. These results support a role of GluA3 in the modulation of social behavior through brain dopamine and/or serotonin signaling and different AMPA receptor subunits affect social behavior through distinct mechanisms.

Figure 1

Motor and Balance Function of Gria3 -/Y and WT Control Mice in the Rotarod Test. Motor learning and latency to fall of WT (n=13) and Gria3 -/Y (n=12) mice were tested individually on accelerating rotarod. Three trials were conducted each day on three consecutive days for a total of 9 trials. (a) Motor learning: means and SEM of three trials each day for the latency to fall were plotted for the three-day test. Note both WT and Gria3 -/Y mice show motor learning as reflected by longer latency to fall over the three-day test period. Gria3 -/Y exhibited significantly shorter stay on the rotarod during day 1 and day 3 of the test. (b) Latency to fall. Means and SEM for a total of 9 trials were shown WT and Gria3 -/Y cohorts. Note that Gria3 -/Y mice had shorter time of stay on the rotarod as compared to WT. (t-test, * p<0.05).

Figure 2

Aggressive and Nonaggressive Social Behavior of Gria3 -/Y and WT Control Mice in Home Cage Resident Intruder Test. (a) Percentage of mice showing aggressive behavior in Gria3 -/Y (n=13) and WT (n=14) cohorts. (b) means and SEM of duration showing aggression in Gria3 -/Y and WT mice. (c) means and SEM of frequencies of attack in Gria3 -/Y and WT mice (d) means and SEM of the latency to first attack in Gria3 -/Y and WT mice. (e) means and SEM of the duration showing nonaggressive social interaction (sniffing and following) in Gria3 -/Y and WT mice. Chi square test for panel a; student's t-test for panels b-e. * p<0.05; ** p<0.01; *** p<0.001

Figure 3

Dyadic Male-Male Interactions in Neutral Arena for Gria3 -/Y and WT Control Mice. Means and SEM for duration showing aggressive behavior (attacks, tail rattles, and total) and nonaggressive social behavior (sniffing, following, and total) were presented for WT (n=13) and Gria3 -/Y (n=14) mice during 5 min free interaction period. Note the increase in nonaggressive social interaction in Gria3 -/Y mice compared to WT (t-test, ** p<0.01).

Figure 4

Sociality and Preference for Social Novelty of Gria3 -/Y and WT Mice. (a) Sociality. The percentage of total time for a test mouse spent in the quadrant with an empty mesh cage versus the quadrant with a stranger mouse (reference mouse 1) in a mesh cage during 10 min was shown for WT (n=14) and Gria3 -/Y (n=12). (b) Preference for social novelty. The percentage of total time for a test mouse spent in the quadrant with familiar mouse (reference 1) in a mesh cage versus the quadrant with a novel mouse (reference 2) in a mesh cage during 10 min was shown for WT (n=14) and Gria3 -/Y (n=12). Statistical analysis within the same genotype was calculated using t-test (* p<0.05; ** p<0.01). For comparisons between the groups, two-way ANOVA followed by planned t-test post hoc were utilized.

Figure 5

Striatal Monoamine Concentrations of Gria3 -/Y and WT mice. Striatum tissues were dissected from brain of adult Gria3 -/Y and WT control mice. Concentrations of norepinephrine (NE), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) were determined using HPLC, calculated with Breeze software (Waters) and expressed as pg/mg of tissue weight. The means and SEM for WT (n=8) and Gria3 -/Y (n=8) were shown. Statistical analysis was performed using Student's t test and ANOVA followed by Fisher's protected least significant difference (PLSD). Data were presented as mean ± SEM; p<0.05 was considered statistically significant.