Preliminary studies have suggested that γ-aminobutyric acid type A (GABAA) receptors, and potentially the GABAAα5 subtype, are deficient in autism spectrum disorder (ASD). However, prior studies have been confounded by the effects of medications, and these studies did not compare findings across different species. We measured both total GABAAand GABAAα5 receptor availability in two positron emission tomography imaging studies. We used the tracer [11C]flumazenil in 15 adults with ASD and in 15 control individuals without ASD and the tracer [11C]Ro15-4513 in 12 adults with ASD and in 16 control individuals without ASD. All participants were free of medications. We also performed autoradiography, using the same tracers, in three mouse models of ASD: theCntnap2knockout mouse, theShank3knockout mouse, and mice carrying a 16p11.2 deletion. We found no differences in GABAAreceptor or GABAAα5 subunit availability in any brain region of adults with ASD compared to those without ASD. There were no differences in GABAAreceptor or GABAAα5 subunit availability in any of the three mouse models. However, adults with ASD did display altered performance on a GABA-sensitive perceptual task. Our data suggest that GABAAreceptor availability may be normal in adults with ASD, although GABA signaling may be functionally impaired.

Impairments in social interaction and communication, in combination with restricted, repetitive behaviors and interests, define the neurodevelopmental diagnosis of autism spectrum disorder (ASD). The biological underpinnings of ASD are not well known, but the hypothesis of serotonin (5-HT) involvement in the neurodevelopment of ASD is one of the longest standing. Reuptake through the 5-HT transporter (5-HTT) is the main pathway decreasing extracellular 5-HT in the brain and a marker for the 5-HT system, but in vivo investigations of the 5-HTT and the 5-HT system in ASD are scarce and so far inconclusive. To quantify possible alterations in the 5-HT system in ASD, we used positron emission tomography and the radioligand [ 11 C]MADAM to measure 5-HTT availability in the brain of 15 adults with ASD and 15 controls. Moreover, we examined correlations between regional 5-HTT availability and behavioral phenotype assessments regarding ASD core symptoms. In the ASD group, we found significantly lower 5-HTT availability in total gray matter, brainstem, and 9 of 18 examined subregions of gray matter. In addition, several correlations between regional 5-HTT availability and social cognitive test performance were found. The results confirm the hypothesis that 5-HTT availability is lower in the brain of adult individuals with ASD, and are consistent with the theory of 5-HT involvement in ASD neurodevelopment. The findings endorse the central role of 5-HT in the physiology of ASD, and confirm the need for a continued investigation of the 5-HT system in order to disentangle the biology of ASD.

This is the peer reviewed version of the following article:Associations between cognition and serotonin receptor 1B binding in patients with major depressive disorder -A pilot study. Tangen, Ämma; Borg, Jacqueline; Tiger, Mikael; Varnäs, Katarina; Sorjonen, Kimmo; Lindefors, Nils; Halldin, Christer; Lundberg, Johan. Psychiatry Res. 2017 Sep 30;267:15-21. which has been published in its final form at: DOI: http://dx.doi.org/10.1016/j.pscychresns. 2017.06.001 This article may be used for non-commercial purposes in accordance with Elsevier Terms and Conditions for selfarchiving. Publisher: ElsevierTitle Associations between cognition and serotonin receptor 1B binding in patients with major 1 depressive disorder -a pilot study 2 3Article type Full Length Article 4 5 Abstract 6The neurotransmitter serotonin has been widely implicated in the pathophysiology of major 7 depressive disorder (MDD). In animal studies and human neuroimaging studies, involvement of 8 the serotonin receptor 1B (5-HT1BR) in MDD and memory performance has been reported. 9However, the role of the 5-HT1BR in cognitive functions affected in MDD remains to be 10 clarified. Ten patients with MDD diagnosis were examined with positron emission tomography 11 (PET) and a battery of cognitive tests before and after Internet-based Cognitive Behavioral 12 Therapy (ICBT). The results were compared to ten matched control subjects in order to 13 investigate putative changes in 5-HT1BR availability and cognitive performance. Patients treated 14 with ICBT showed statistically significant improvement relative to baseline in Verbal fluency, 15 both letter and category production. Significant correlations were found between improvement in 16 letter production and changes in 5-HT1BR availability in ventral striatum, between category 17 production and amygdala, as well as between the improvement in Trailmaking test B and change 18 in 5-HT1BR binding in dorsal brainstem, in amygdala and in hippocampus. Introduction 40Major depressive disorder (MDD) has a lifetime prevalence of 11-15 % (Bromet et al., 41 2011) and is the leading cause of disability worldwide (World Health Organization, 2017). It is a 42 clinically heterogeneous disease of variable course in which the core symptoms, low mood and 43 loss of interest, are related to emotional dysregulation. Recent research has demonstrated that also 44 cognitive impairments play an important role in the symptomatology of MDD (Rock et al., 2014; 45 Trivedi and Greer, 2014). These include reversible dysfunctions that largely normalize after a 46 major depressive episode, that is, visuospatial short term memory function (Behnken et al., 47 2010), and persistent cognitive impairments remaining after remission, such as attention and 48 executive functions (Rock et al., 2014; Årdal and Hammar, 2011). In a meta-analysis 49 investigating executive function in 375 depressed patients and 481 control subjects, patients were 50found to perform significantly worse in tasks measuring semantic verbal fluency, cognitiv...