Journal
BEHAVIOURAL BRAIN RESEARCH
Volume 359, Issue -, Pages 918-926Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbr.2018.06.019
Keywords
Serotonin; Tryptophan hydroxylase 2; Dorsal raphe nucleus; Autism
Categories
Funding
- La Trobe University Research Focus Area: Understanding Disease
- Australian Postgraduate Award
- Australian Research Council [DE140101075]
- Department of the Navy, Office of Naval Research Multidisciplinary University Research Initiative (MURI) Award [N00014-15-1-2809]
- Department of Veterans Affairs Office of Research and Development (VA-ORD) RR&D Small Projects in Rehabilitation Research (SPiRE) [1 I21 RX002232-01]
- Colorado Clinical & Translational Sciences Institute (CCTSI) Center for Neuroscience [CNSTT-15-145]
- Colorado Department of Public Health and Environment (CDPHE) [DCEED-3510]
- Alfred P. Sloan Foundation [G-2016-7077]
- Australian Research Council [DE140101075] Funding Source: Australian Research Council
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Autism spectrum disorder (ASD) is a heterogeneous and highly heritable condition with multiple aetiologies. Although the biological mechanisms underlying ASD are not fully understood, evidence suggests that dysregulation of serotonergic systems play an important role in ASD psychopathology. Preclinical models using mice with altered serotonergic neurotransmission may provide insight into the role of serotonin in behaviours relevant to clinical features of ASD. For example, BALB/c mice carry a loss-of-function single nucleotide polymorphism (SNP; C1473 G) in tryptophan hydroxylase 2 (Tph2), which encodes the brain-specific isoform of the rate-limiting enzyme for serotonin synthesis, and these mice frequently have been used to model symptoms of ASD. In this study, juvenile male BALB/c (G/G; loss-of-function variant) and C57BL/6 J (C/C; wild type variant) mice, were exposed to the three-chamber sociability test, and one week later to the elevated plus-maze (EPM). Tryptophan hydroxylase 2 (TPH2) activity was measured following injection of the aromatic amino acid decarboxylase (AADC)-inhibitor, NSD-1015, and subsequent HPLC detection of 5-hydroxytryptophan (5-HTP) within subregions of the dorsal raphe nucleus (DR) and median raphe nucleus (MnR). The BALB/c mice showed reduced social behaviour and increased anxious behaviour, as well as decreased 5-HTP accumulation in the rostral and mid-rostrocaudal DR. In the full cohort of mice, TPH2 activity in the mid-rostrocaudal DR was correlated with anxious behaviour in the EPM, however these correlations were not statistically significant within each strain, suggesting that TPH2 activity was not directly associated with either anxiety or sociability. Further research is therefore required to more fully understand how serotonergic systems are involved in mouse behaviours that resemble some of the clinical features of ASD.
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