Autism Spectrum Disorders: Multiple Routes to, and Multiple Consequences of, Abnormal Synaptic Function and Connectivity

Abstract

Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders of genetic and environmental etiologies. Some ASD cases are syndromic: associated with clinically defined patterns of somatic abnormalities and a neurobehavioral phenotype (e.g., Fragile X syndrome). Many cases, however, are idiopathic or non-syndromic. Such disorders present themselves during the early postnatal period when language, speech, and personality start to develop. ASDs manifest by deficits in social communication and interaction, restricted and repetitive patterns of behavior across multiple contexts, sensory abnormalities across multiple modalities and comorbidities, such as epilepsy among many others. ASDs are disorders of connectivity, as synaptic dysfunction is common to both syndromic and idiopathic forms. While multiple theories have been proposed, particularly in idiopathic ASDs, none address why certain brain areas (e.g., frontotemporal) appear more vulnerable than others or identify factors that may affect phenotypic specificity. In this hypothesis article, we identify possible routes leading to, and the consequences of, altered connectivity and review the evidence of central and peripheral synaptic dysfunction in ASDs. We postulate that phenotypic specificity could arise from aberrant experience-dependent plasticity mechanisms in frontal brain areas and peripheral sensory networks and propose why the vulnerability of these areas could be part of a model to unify preexisting pathophysiological theories.

Precision Autism: Genomic Stratification of Disorders Making Up the Broad Spectrum May Demystify Its “Epidemic Rates”

“…The increase in neurodevelopmental disabilities is real, as evidenced by the compact set of genes identified to be common to SFARI-Autism and all other diseases under consideration. All these genes play a fundamental role on the development of synapses via proteins that are necessary for channels functioning and neurotransmitters balance, neuronal differentiation, the formation of circuits and networks, etc., during neurodevelopment [93]. Yet, these disorders exist independent of Autism.…”

Spatiotemporal dynamics of human microglia are linked with brain developmental processes across the lifespan

“…The elucidation of microglial dynamics during human cortical development offers new avenues for examining how these cells contribute to neurodevelopmental disorders. These cells participate in brain wiring pre- and postnatally (Menassa and Gomez-Nicola, 2018; Paolicelli et al, 2011; Squarzoni et al, 2014) and are involved in the pathophysiology of autism spectrum disorder (Carroll et al, 2021; Tetreault et al, 2012), schizophrenia (Sekar et al, 2016), and intellectual disability (Coutinho et al, 2017). With our identification of critical temporal windows of the population’s expansion and refinement, we pave the way for novel uncharted territories in the field of neurodevelopmental disorders, which, with the current tissue resources in place, may begin to closely characterise in space and time how the population alters the neurodevelopmental environment.…”

Precision Autism: Genomic Stratification of Disorders Making Up the Broad Spectrum May Demystify its “Epidemic Rates”

“…The increase in neurodevelopmental disabilities (including intellectual disability) is as real as it gets, as evidenced by the compact set of genes identified to be common to SFARI-Autism and all other diseases under consideration. All these genes play a fundamental role on the development of synapses via proteins that are necessary for channels functioning and neurotransmitters balance, neuronal differentiation, the formation of circuits and networks, etc., during neurodevelopment [81]. Yet, these disorders exist independent of Autism.…”