Autism spectrum disorder: neuropathology and animal models

Abstract

Autism spectrum disorder (ASD) has a major impact on the development and social integration of affected individuals and is the most heritable of psychiatric disorders. An increase in the incidence of ASD cases has prompted a surge in research efforts on the underlying neuropathologic processes. We present an overview of current findings in neuropathology studies of ASD using two investigational approaches, postmortem human brains and ASD animal models, and discuss the overlap, limitations and significance of each. Postmortem examination of ASD brains has revealed global changes including disorganized gray and white matter, increased number of neurons, decreased volume of neuronal soma, and increased neuropil, the last reflecting changes in densities of dendritic spines, cerebral vasculature and glia. Both cortical and non-cortical areas show region-specific abnormalities in neuronal morphology and cytoarchitectural organization, with consistent findings reported from the prefrontal cortex, fusiform gyrus, frontoinsular cortex, cingulate cortex, hippocampus, amygdala, cerebellum and brainstem. The paucity of postmortem human studies linking neuropathology to the underlying etiology has been partly addressed using animal models to explore the impact of genetic and non-genetic factors clinically relevant for the ASD phenotype. Genetically modified models include those based on well-studied monogenic ASD genes (NLGN3, NLGN4, NRXN1, CNTNAP2, SHANK3, MECP2, FMR1, TSC1/2), emerging risk genes (CHD8, SCN2A, SYNGAP1, ARID1B, GRIN2B, DSCAM, TBR1), and copy number variants (15q11-q13 deletion, 15q13.3 microdeletion, 15q11-13 duplication, 16p11.2 deletion and duplication, 22q11.2 deletion). Models of idiopathic ASD include inbred rodent strains that mimic ASD behaviors as well as models developed by environmental interventions such as prenatal exposure to sodium valproate, maternal autoantibodies and maternal immune activation. In addition to replicating some of the neuropathologic features seen in postmortem studies, a common finding in several animal models of ASD is altered density of dendritic spines, with the direction of the change depending on the specific genetic modification, age and brain region. Overall, postmortem neuropathologic studies with larger sample sizes representative of the various ASD risk genes and diverse clinical phenotypes are warranted to clarify putative etiopathogenic pathways further and to promote the emergence of clinically relevant diagnostic and therapeutic tools. In addition, as genetic alterations may render certain individuals more vulnerable to developing the pathological changes at the synapse underlying the behavioral manifestations of ASD, neuropathologic investigation using genetically modified animal models will help to improve our understanding of the disease mechanisms and enhance the development of targeted treatments.

Maternal immune activation in neurodevelopmental disorders

“…Adult reduction in the expression of presynaptic (synaptophysin) and postsynaptic (PSD-95) proteins was also reported in models of MIA (Hao et al, 2010;Meyer, 2013;Giovanoli et al, 2016b), both neuropathological hallmarks of disorders such as ASD and schizophrenia (Penzes et al, 2011;Varghese et al, 2017). Vesicle-associated membrane protein (VAMP)-1 levels are higher in brain tissue from Poly(I:C)-treated juvenile (P21) animals, but synaptotagmin and synaptophysin levels are unchanged (Forrest et al, 2012).…”

Clustering by phenotype and genome-wide association study in autism

“…In addition to genes in the Human Gene module of the SFARI Gene, several important genes associated with ASD or other related disorders (34-37) from previous reports were included in our findings as follows: CDH5 in Cluster 14, DSCAM in Cluster 8, FOXK1 in Cluster 13, GRIN2A in Cluster 5, NTM in Cluster 8, and SNCA in Cluster 11 previously reported with ASD (38)(39)(40)(41)(42)(43); PLCH2 in Cluster 11 previously reported with mental retardation (44);…”

The neuropathological investigation of the brain in a monkey model of autism spectrum disorder with ABCA13 deletion

“…Various findings have been reported in the study of the neuropathology and neuroanatomy of ASD, but no reliable diagnostic markers have yet been found. However, influential findings, such as changes in the frontal lobe volume during the developmental stage (based on neuroimaging), synaptic dysplasia, failure of the neurotransmission function, glial and/or myelin dysplasia, and similar changes (based on neuropathological studies) have been revealed (see reviews by Varghese et al, Amaral et al, and Courchesne et al) (Amaral et al, 2008;Courchesne et al, 2011;Varghese et al, 2017). It is thought that the heterogeneity of the findings may reflect that multiple genetic factors (not a single gene) are associated with ASD.…”