Understanding intellectual disability and autism spectrum disorders from common mouse models: synapses to behaviour

Abstract

Normal brain development is highly dependent on the timely coordinated actions of genetic and environmental processes, and an aberration can lead to neurodevelopmental disorders (NDDs). Intellectual disability (ID) and autism spectrum disorders (ASDs) are a group of co-occurring NDDs that affect between 3% and 5% of the world population, thus presenting a great challenge to society. This problem calls for the need to understand the pathobiology of these disorders and to design new therapeutic strategies. One approach towards this has been the development of multiple analogous mouse models. This review discusses studies conducted in the mouse models of five major monogenic causes of ID and ASDs: Fmr1, Syngap1, Mecp2, Shank2/3 and Neuroligins/Neurnexins. These studies reveal that, despite having a diverse molecular origin, the effects of these mutations converge onto similar or related aetiological pathways, consequently giving rise to the typical phenotype of cognitive, social and emotional deficits that are characteristic of ID and ASDs. This convergence, therefore, highlights common pathological nodes that can be targeted for therapy. Other than conventional therapeutic strategies such as non-pharmacological corrective methods and symptomatic alleviation, multiple studies in mouse models have successfully proved the possibility of pharmacological and genetic therapy enabling functional recovery.

Distinct synaptic and related transcriptional abnormalities in neonatal, childhood and mature autism model of primate: implications for early-age therapeutic intervention

“…The altered E/I ratio in VPA animals observed at 3M suggested downregulation of excitatory synapses at this age; moreover, there might be abnormal regulatory mechanisms of excitatory synapses. Previous studies on ASD model rodents have reported that long-term depression (LTD) is affected 23 . To determine whether VPA exposure affected LTD of excitatory synapses, we recorded the field EPSPs in layer 3 evoked by layer 4-5 stimulation, and induced LTD by low frequency stimulation (LFS, 1 Hz, 15 min).…”

Dysfunction of the corticostriatal pathway in autism spectrum disorders

“…ASD, the most prevalent neurodevelopmental disorders, is used to define a clinically heterogeneous group of disorders, while it generally exhibits two core symptoms, impaired social communication and repetitive behaviors (Bhat, Acharya, Adeli, Bairy, & Adeli, 2014;Fakhoury, 2015). A large number of risk genes that are associated with ASD pathogenesis have been identified (Nakanishi, Anderson, & Takumi, 2019;Verma, Paul, Amrapali Vishwanath, Vaidya, & Clement, 2019). Studies on ASD-related genes have indicated an altered axonal growth, an imbalance in neural network excitation/inhibition, and an impaired synaptic plasticity in the corticostriatal pathway (Fuccillo, 2016;Golden, Buxbaum, & De Rubeis, 2018;Kuo & Liu, 2019;Shepherd, 2013).…”

Intellectual disability, the long way from genes to biological mechanisms

“…For example, genes that encode physically interacting proteins, which are co-regulated or co-evolving, are more likely to work in a common process. In addition, studies on single gene mouse models of ID reveal that the effects of these mutations converge onto similar or related etiological pathways, highlighting common pathological nodes that can help in the understanding of new ID related genes [28] . The huge collection of mutant model organisms and the literature can be reviewed to study ID related phenotypes, keeping in mind the mode of inheritance demonstrated in humans when choosing the model to study.…”