Drug-responsive autism phenotypes in the 16p11.2 deletion mouse model: a central role for gene-environment interactions

Abstract

There are no current treatments for autism, despite its high prevalence. Deletions of chromosome 16p11.2 dramatically increase risk for autism, suggesting that mice with an equivalent genetic rearrangement may offer a valuable model for the testing of novel classes of therapeutic drug. 16p11.2 deletion (16p11.2 DEL) mice and wild-type controls were assessed using an ethological approach, with 24 h monitoring of activity and social interaction of groups of mice in a home-cage environment. The ability of the excitation/inhibition modulator N-acetyl cysteine (NAC) and the 5-HT 1B/1D/1F receptor agonist eletriptan to normalise the behavioural deficits observed was tested. 16p11.2 DEL mice exhibited largely normal behaviours, but, following the stress of an injection, showed hyperlocomotion, reduced sociability, and a strong anxiolytic phenotype. The hyperactivity and reduced sociability, but not the suppressed anxiety, were effectively attenuated by both NAC and eletriptan. The data suggest that 16p11.2 DEL mice show an autism-relevant phenotype that becomes overt after an acute stressor, emphasising the importance of gene-environmental interactions in phenotypic analysis. Further, they add to an emerging view that NAC, or 5-HT 1B/1D/1F receptor agonist treatment, may be a promising strategy for further investigation as a future treatment. Autism is extremely common, affecting males more than females (estimated to affect roughly 4/1,000 boys and 1/1,000 girls) 1,2 , and characterised by communication difficulties, social dysfunction, and repetitive or restricted behaviour patterns, with a high rate of comorbid conditions such as anxiety. There are no available drug treatments for autism. Development of improved treatments will only be enabled by increased understanding of the causes of the disease and how they impact on neurobiology, informed by better preclinical models of facets of the disease. The genetic architecture of autism is complex 3. While a large number of common sequence variations increase disease risk, each has only a very small effect individually, and it is the cumulative burden of a range of risk, and protective, gene variants that underlies the aetiological mechanisms ultimately resulting in the manifestation of the common, sporadic disease. However, it is now clear that very rare copy number variants (CNVs), where small numbers of genes are present in one or three, rather than two, copies, substantially increase disease risk. For example, carriers of the deletions of the 16p11.2 locus have dramatically increased risk of autism-spectrum disorders (ASD) and also intellectual disability (8-40x) 4-6. Interestingly, a high proportion of carriers of the corresponding 16p11.2 duplication develop schizophrenia, suggesting that studying the neurobiological impact of CNVs at this locus may be particularly informative. The 16p11.2 deletion is one of the most powerful genetic risk factors for autism 3. Various drug classes have been tested in mouse models relevant to ASD, for efficacy in reversing behavioural...

The Potential of N-Acetyl-L-Cysteine (NAC) in the Treatment of Psychiatric Disorders

“…On dissection, the glutaminergic system in the amygdala of the NAC-treated rats normalized, and their social interactions improved [ 25 ]. Mice with deletions of chromosome 16p11.2, which is associated with ASD in humans, exhibited ASD phenotype (slowed hyperlocomotion, reduced sociability, and displayed a strong anxiolytic phenotype) when under stress [ 26 ]. A single dose of NAC (150 mg/kg) did not normalize the anxiety-like behaviors but did increase sociability [ 26 ].…”

Mice lacking melatonin MT2 receptors exhibit attentional deficits, anxiety and enhanced social interaction

“…A radiofrequency identification (RFID) transponder was implanted subcutaneously under isoflurane anaesthesia, and a minimum of 24 h later, groups of three mice were transferred to a Home-Cage Analyser (Actual Analytics Ltd., Edinburgh, UK). After an initial 1.5 h prior to habituate, mice were monitored for 72 h (recording commenced at 10 am – onset of dark phase) ( Bristow et al, 2020 ; Mitchell et al, 2020b ). One cage (three WT females) was subsequently excluded from the analysis due to technical issues.…”

N‐acetylcysteine as a new prominent approach for treating psychiatric disorders

“…prevented anxiety induced by rhythm disruption in mice (Pilz et al, 2015). Deletions of the 16p11.2 locus, which is related to an increased risk of autism spectrum disorders, were associated with an anxiolytic response in mice (Mitchell et al, 2020). The administration of NAC (150 mg kg −1 ; i.p.)…”

“…The administration of NAC (150 mg kg −1 ; i.p.) 15 min prior to the onset of the dark period did not normalize the anxiety‐like behaviours in either mutant or control mice (Mitchell et al, 2020).…”