Differences in the expression of restricted repetitive behaviors in female and male BTBR T + tf/J mice.

Autism spectrum disorder (ASD) is characterized by the expression of restricted repetitive behaviors (RRBs) and impairments in social recognition and communication. Epidemiological studies demonstrate males are three times more likely than females to be affected. Although this is the case, more recent studies suggest females may be underrepresented in these numbers due to standard clinical measures of RRBs and social behaviors. In addition, many studies examining mouse models of ASD exclude females due to the sex disparity in diagnoses. The present study examined how female and male BTBR T + Itpr3tf /J (BTBR) compare to control C57BL/6J mice on tests of RRBs (probabilistic reversal learning, repetitive grooming, spontaneous alternation, and marble burying) and social behaviors (three chambered social approach task). Utilizing a spatial reversal learning test with 80/20 probabilistic feedback, in which ASD individuals have exhibited deficits, we find that female BTBR mice do not show the same impairment found in male BTBR mice. Interestingly, control female C57BL/6J mice required more trials to reach criterion. Female BTBR mice expressed comparable rates of repetitive grooming, marble burying and spontaneous alternation compared to female C57BL/6J mice. Male BTBR mice expressed higher rates of grooming behavior and locomotor activity compared to male C57BL/6J mice, as found in previous studies. Similarly, male BTBR mice showed a reduction in both measures of social approach compared to controls. Both male and female BTBR mice showed a reduction in sniff time for the stranger mouse compared to controls. Together these findings demonstrate how female BTBR mice do not display the RRB profile expressed by male BTBR mice. Testing of repetitive behaviors in ASD needs to better reflect the sex differences in how RRBs manifest in females compared to their extensively researched male counterparts.

5-HT6 receptor agonist EMD386088 impairs behavioral flexibility and working memory.

Serotonin 6 (5-HT6) receptors are primarily expressed in the central nervous system and to an even further extent brain regions responsible for learning and memory. Recent studies have demonstrated 5-HT6 receptor involvement in pathophysiological processes highlighting their therapeutic possibilities. Most research concerning the effects of 5-HT6 receptor modulation has focused on blockade despite paradoxical findings that 5-HT6 agonists and antagonists can both have pro-cognitive effects. The current experiments examine the effects of the 5-HT6 receptor agonist EMD386088 on behavioral flexibility and working memory. C57BL/6J mice received systemic injections of either 0, 2, or 4 mg/kg EMD386088 before being tested on probabilistic reversal learning, spontaneous alternation, and locomotor activity. In the probabilistic reversal learning task, the high dose of 4 mg/kg significantly impaired performance requiring more trials to reach criterion. The same dose significantly increased perseverative type errors, suggesting that the probabilistic reversal learning impairment was due to an inability to inhibit the previously learned choice pattern, rather than maintaining the new optimal choice pattern. Acute EMD386088 administration at 2 mg/kg significantly impaired spontaneous alternation performance, while the high dose of 4 mg/kg did not reach significance. These learning impairments were not due to an overall locomotor impairment as evidenced by comparable locomotor activity scores. Acute systemic 5-HT6 receptor activation with EMD386088 led to impaired behavior flexibility and working memory performance. Current findings support previous research suggesting that novel therapeutics directed at down regulation of 5-HT6 receptors may be effective in attenuating working memory and behavioral flexibility impairments commonly found in neuropsychiatric disorders such as Alzheimer's and schizophrenia.