The utility of rodent models of autism spectrum disorders

Abstract

Purpose of Review This review discusses the ways rodent models of autism spectrum disorders (ASDs) have been used to gain critical information convergent molecular pathways, the mechanisms underlying altered microcircuit structure and function, and as a screen for potential cutting edge-treatments. Recent Findings There is convergent evidence that impaired developmental pruning of connections may be a common finding among several mouse models of ASDs. Recent studies have uncovered impaired autophagy by pathological mTOR activation as a potential contributor to microcircuit dysfunction and behavior. ASD related disinhibition and exaggerated synaptic plasticity in multiple distinct circuits in cortex and reward circuits in striatum also contribute to social dysfunction and repetitive behaviors. New exciting molecular therapeutic techniques have reversed cognitive deficits in models of ASD, indicating that mouse models could be used for preclinical translational studies of new treatments. Summary Rodent models of ASDs coupled to new emerging technologies for genome editing, cell-specific functional and structural imaging, and neuronal activity manipulation will yield critical insights into ASD pathogenesis and fuel the emergence of new treatments.

Cortical excitation:inhibition imbalance causes abnormal brain network dynamics as observed in neurodevelopmental disorders

“…Moreover, FC architecture predicts individual differences in task-dependent activity (Tavor; and is sensitive to neuropsychiatric conditions in both human patients , Balsters et al, 2017 and mouse models of brain disorders (M. G. Haberl et al, 2015, Zerbi et al, 2018a. These properties have contributed to rsfMRI becoming an increasingly popular measurement in clinical populations (Kraguljac et al, 2016, Kennedy and Adolphs, 2012, Kahan et al, 2014 and for translational research (Grayson et al, 2016, Zerbi et al, 2018b, Sforazzini et al, 2016, Lazaro and Golshani, 2015. Interestingly, patients with Autism Spectrum Disorder (ASD) and genetically manipulated mouse models mimicking this condition display similar aberrations of long-range connectivity in plausible mouse-human homologue networks, suggesting a mechanistic link between genetic risk for neurodevelopmental disorders and long-range functional decoupling , Scott-Van Zeeland et al, 2010, Zerbi et al, 2018b.…”

Exploiting aberrant mRNA expression in autism for gene discovery and diagnosis

“…A total of 18 GSEA curated gene sets were found to produce significantly higher SSMD than random gene sets at FDR of 10 %. The dysregulation of this pathway is implicated in ASD (Abrahams and Geschwind 2008;Lazaro and Golshani 2015;Sawicka and Zukin 2012). The relevance of these major functional categories with ASD is supported by respective studies (Abrahams and Geschwind 2008;Chow et al 2012;Frye et al 2010;Klaiman et al 2013;Lazaro and Golshani 2015;Sawicka and Zukin 2012;Tierney et al 2006).…”

“…These included the curated gene sets in the MSigDB of GSEA (Liberzon et al 2011). The relevance of these major functional categories with ASD is supported by respective studies (Abrahams and Geschwind 2008;Chow et al 2012;Frye et al 2010;Klaiman et al 2013;Lazaro and Golshani 2015;Sawicka and Zukin 2012;Tierney et al 2006). A total of 18 GSEA curated gene sets were found to produce significantly higher SSMD than random gene sets at FDR of 10 %.…”

The dog (Canis familiaris) as a translational model of autism: It is high time we move from promise to reality

“…The fact that both proximate and ultimate mechanisms underlying the development of the autistic behaviors remain to be refined poses an acute problem for autism research, and stresses the need for animal models that may advance our understanding of the disease mechanisms. The traditional rodent models boast an impressive array of experimental evidence (Lazaro & Golshani, 2015), the molecular genetics models of ASD are precise and tractable (Watson & Platt, 2012) and some of the core features of human autism can be simulated in mice (Bicks, Koike, Akbarian, & Morishita, 2015). Importantly, however, this approach suffers from significant limitations.…”