No prominent role for complement C1-esterase inhibitor in Marfan syndrome mice.

Marfan syndrome (MFS) is a connective tissue disorder causing aortic aneurysm formation. Currently, only prophylactic aortic surgery and blood pressure-lowering drugs are available to reduce the risk of aortic rupture. Upon whole genome sequencing of a Marfan family, we identified a complement gene C1R variant (p.Ser152Leu), which is associated with severe aortic patients. Therefore, we assessed the role of complement activation in MFS aortic tissue. Expression of various complement genes and proteins was detected in human and murine MFS aneurysm tissue, which prompted us to study complement inhibition in MFS mice. Treatment of the Fbn1C1041G/+ MFS mice with human plasma-derived C1-esterase inhibitor Cetor® resulted in reduced complement deposition, decreased macrophage influx in the aorta, and lower circulating TNFα levels. However, in line with previous anti-inflammatory treatments, complement inhibition did not change the aortic dilatation rate in this MFS mouse model. Thus, while complement factors/component 3 activation were detected in human/murine MFS aorta, Cetor® had no effect on aortic dilatation in MFS mice, indicating that complement inhibition is not a suitable treatment strategy in MFS.

Examination of the effects of cannabinoid ligands on decision making in a rat gambling task.

Although exposure to delta-9-tetrahydrocannabinol (THC) is perceived to be relatively harmless, mounting evidence has begun to show that it is associated with a variety of cognitive deficits, including poor decision making. THC-induced impairments in decision making are thought to be the result of cannabinoid CB1 receptor activation, and although clinical literature suggests that chronic activation via THC contributes to perturbations in decision making, acute CB1 receptor modulation has yielded mixed results. Using an animal model to examine how CB1-specific ligands impact choice biases would provide significant insight as to how recruitment of the endocannabinoid system may influence decision making. Here, we used the rat gambling task (rGT), a validated analogue of the human Iowa Gambling Task, to assess baseline decision making preferences in male Wistar rats. After acquisition rGT performance was measured. Animals were challenged with the CB1 receptor antagonist rimonabant, the partial agonist THC, and the synthetic agonist WIN55,212-2. Animals were also treated acutely with the fatty acid amide hydrolase (FAAH) inhibitor URB597 to selectively upregulate the endocannabinoid anandamide. Blockade of the CB1 receptor produced a trend improvement in decision making in animals who preferred the advantageous task options, yet left choice unaffected in risk-prone rats. Neither CB1 receptor agonist had strong effects on decision making, but a high dose THC decreased premature responses, whereas WIN55,212-2 did the opposite. URB597 did not affect task performance. These results indicate that although chronic CB1 receptor activation may be associated with impaired decision making, acute modulation has modest effects on choice and instead may play a substantive role in regulating impulsive responding.

Prefrontal cortical neuregulin-ErbB modulation of inhibitory control in rats.

Impulse control disturbances are key features of various neuropsychiatric and neurological disorders, such as attention-deficit/hyperactivity disorder, drug addiction, Parkinson disease and schizophrenia. Whereas over the last years accumulating evidence has highlighted monoaminergic modulation of the processes underlying impulse control, investigating novel mechanisms beyond monoamines may provide new intervention strategies to ameliorate impulse control disturbances. Recent work has associated the neuregulin (Nrg)-ErbB pathway with several neuropsychiatric diseases, as well as indicated its involvement in murine measures of impulse control. The aim of the present study was to investigate whether this Nrg-ErbB signaling pathway also modulates impulsive action in rats. To this end, a group of rats was trained in the 5-choice serial reaction time task (5-CSRTT), an operant paradigm that provides measures of visuospatial attention and inhibitory control processes. Upon stable baseline performance, the ErbB tyrosine kinase receptor inhibitor JNJ-28871063 (JNJ) was intracranially infused into the medioprefrontal cortex prior to test sessions. Results showed that JNJ dose-dependently improved measures of impulsive action. Importantly, other measures in the 5-CSRTT reflecting visuospatial attention or aspects of motivational behavior were not altered by JNJ. In conclusion, the present data strengthen a role for the Nrg-ErbB4 pathway in the prefrontal cortex in cognitive functioning, and in particular point towards involvement in the processes underlying impulse control.