Investigation of peripheral nerve sensitivity in two animal models of Autism Spectrum Disorder (ASD)

Abstract

Introduction: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterised by deficits in social communication and restricted behaviours, and associated with sensory alterations, gastrointestinal dysfunction and disruptions in the circadian rhythm. This study utilised two animal models of ASD, the BTBR T+tf/J and the prenatal exposure to VPA mouse models of ASD, compared to the control C57 BL/6J strain. The aim of this study was to investigate changes in circadian rhythm and peripheral sensation in the two mouse models of ASD, and identify potential pathways involved.

Methods: Home-cage testing was conducted using LABORAS platforms, to record the animals’ behaviour over 24 hours (C57 n = 8; BTBR = 9, VPA = 4). Cutaneous sensory thresholds were determined using the dynamic hot (DHP) and cold plate (DCP) tests (C57 n = 6; BTBR n = 6; VPA n = 4), and sensory function of the gastrointestinal tract was outlined using ex-vivo jejunum preparations, by recording the afferent nerve responses to mechanical and chemical stimuli. Values are mean +/- SEM analysed with two-way ANOVA using GraphPad Prism.

Results: the VPA mice exhibited altered circadian rhythm in the dark (active) phase compared to the BTBR and C57 mice (P=<0.05). In the DHP, the BTBR mice (n = 6) responded at a higher temperature (C57 - 38C; BTBR - 40C), responded significantly less to heat
(P<0.0005), while VPA mice (n = 4) showed similarresponses to the C57 mice. In the DCP, VPA mice start to respond at a lower temperature (C57 - 16C; VPA - 2C), responded slightly less to cold (P=0.055), while the BTBR mice showed similar responses to C57 mice.
In the afferent nerve recordings of the jejunum, the BTBR tissue exhibited significantly decreased responses to mechanical distension at a filling rate of 600 µl/min (P<0.0006; BTBR n = 9; C57 n = 10). Peak firing rate at 50 mmHg was 92.68 (+/- 12.80) imp/s-1 in recordings from C57 (n = 10) tissue and 76.49 (+/- 15.44) imp/s-1 in BTBR tissue (n = 9). BTBR afferents also showed an altered response profile to TRPV1 activation (P=<0.0001, BTBR n = 5; C57 n = 5), whereby nerve firing took significantly longer to desensitize compared to control afferents, suggesting altered function of TRPV1. Preparations from BTBR mice also exhibited significantly increased response to intraluminal application of an inflammatory soup (P<0.05), BTBR n = 5; C57 n = 5).

Conclusion: the VPA model of ASD showed marked alterations in circadian rhythm and reduced response to cold stimuli, and the BTBR mouse model of ASD exhibited significantly decreased response to heat and significantly altered afferent nerve activity from the jejunum in response to various stimuli. Future studies should investigate whether these changes correlate with CNS dysfunction or whether altered peripheral sensation could drive some of the central deficits observed in ASD.