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.

Keywords: autism spectrum disorders; connectivity; maternal immune activation; neurodevelopment; pain sensitivity; phenotypic specificity; synaptic dysfunction; synaptic plasticity.

Figure 1.

Timing of human neurogenetic events. These events can be affected by genetic and environmental factors during prenatal and postnatal periods, leading to abnormal cortical organization and complex cognitive and behavioral deficits in humans. The critical period for the interaction of presynaptic axons and postsynaptic neurons during initial synaptogenesis and the formation of cortical circuitry begins at the early fetal period and shows prolonged periods of prospective vulnerability: during the early preterm for thalamocortical connections (red bar), and during the late preterm for callosal and long cortico-cortical connections (blue), which may correspond to a 1st hit event. However, since short cortico-cortical pathways continue during infancy and early childhood (purple), peaking at around 2 years for associative cortex for example, we may expect vulnerability that corresponds to a second hit in the pathogenesis of circuitry relating to ASD. Modified with permission from Kostović I, Judaš M. (2015). Embryonic and fetal development of the human cerebral cortex in brain mapping: an encyclopaedic reference; volume 2: anatomy and physiology, systems, Elsevier.

Figure 2.

Dysfunction of primary sensory neurons in autism spectrum disorders (ASD). By genetically altering ASD-linked genes, several mouse models have been developed. Some of these models have shown phenotypic changes in somatosensation associated with primary sensory neuron dysfunction. This dysfunction is linked not only to the synapse (the central terminal of the dorsal horn of the spinal cord) of these neurons but also to other neuronal compartments (e.g., the peripheral terminal in the skin and the cell soma). Loss of Cntnap2 leads to hyperexcitability in d-hairs, a type of low threshold mechanoreceptor (LTMR), due to loss of Kv1 channel function. Loss of Shank3 reduces the functional expression of TRPV1, a transduction channel important in heat hyperalgesia, in nociceptors. Soma loss of Cntnap2 also impacts onto nociceptor function resulting in hyperexcitablility of Aδ and C fibers. At the level of the synapse, loss of MECP2 results in the down regulation of GABA receptors and loss of presynaptic inhibition on LTMRs leading to increased sensitivity to tactile stimuli.

Figure 3.

Connectivity in autism spectrum disorders (ASD). Left: spatial and temporal resolutions of common neuroimaging technologies used in measuring connectivity in ASD. Right: an illustration of the putative anomalies in functional connectivity in ASD, where local connections are favored over long-range interactions. MEG, magnetoencephalography; EEG, electroencephalography; fMRI, functional magnetic resonance imaging; PET, positron emission tomography; SPECT, single-photon emission computed tomography; IEEG, intracranial electric recordings.