Role of Oligodendrocytes and Myelin in the Pathophysiology of Autism Spectrum Disorder

Abstract

Autism Spectrum Disorder (ASD) is an early neurodevelopmental disorder that involves deficits in interpersonal communication, social interaction, and repetitive behaviors. Although ASD pathophysiology is still uncertain, alterations in the abnormal development of the frontal lobe, limbic areas, and putamen generate an imbalance between inhibition and excitation of neuronal activity. Interestingly, recent findings suggest that a disruption in neuronal connectivity is associated with neural alterations in white matter production and myelination in diverse brain regions of patients with ASD. This review is aimed to summarize the most recent evidence that supports the notion that abnormalities in the oligodendrocyte generation and axonal myelination in specific brain regions are involved in the pathophysiology of ASD. Fundamental molecular mediators of these pathological processes are also examined. Determining the role of alterations in oligodendrogenesis and myelination is a fundamental step to understand the pathophysiology of ASD and identify possible therapeutic targets.

Keywords: epidermal growth factor; insulin-like growth factor; myelination; oligodendrogenesis.

Figure 1

Cortical areas, subcortical areas and white matter tracts affected in patients with Autism Spectrum Disorder (ASD). White matter areas with the most noticeable changes are represented in the three anatomical planes of the human brain: axial, sagittal, and coronal, respectively. Brain schemes also indicate the most common myelination changes that occur in ASD patients during two different stages of development [21,30,36,60,64,65,67,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109]. acg: anterior cingulate gyrus; afp: amygdala-fusiform pathway; Amy: amygdala; atr: anterior thalamic radiation; arc: arcuate fasciculus; CB: cerebellum; cb: cingulum bundle; cc: corpus callosum; c.s.t.: corticospinal tract; cr: corona radiata; exc: external capsule; fm: forceps minor; fx: fornix; fg: fusiform gyrus; hipp: hippocampus; icp: inferior cerebellar peduncle; ifof: inferior fronto-occipital fasciculus; ifg: inferior frontal gyrus; Ins: insula; ic: internal capsule; L-hfp: left hippocampus-fusiform pathway; L-ilf: Left inferior longitudinal fasciculus; L-ofc: left orbitofrontal cortex; lig: lingual gyrus; ml: medial lemniscus; mcp: middle cerebellar peduncle; mtg: middle frontal gyrus; mtg: middle temporal gyrus; off: occipitofrontal fasciculus; otg: occipitotemporal gyrus; pct: pontine crossing tracts; ptr: posterior thalamic radiation; pre: precentral area; PFC: prefrontal cortex; Pu: putamen; slbex: sub-lobar extranuclear area; scp: superior cerebellar peduncle; sfg: superior frontal gyrus; slf: superior longitudinal fasciculus; stg: superior temporal gyrus; sma: supplementary motor area; Tpj: temporoparietal junction; Thm: thalamus; unf: uncinate fasciculus; vtg: ventral temporal gyrus.

Figure 2

Oligodendrocyte lineage and molecular markers (genes or proteins) expressed under physiological and ASD conditions. Each human and mouse illustration indicates whether the molecular abnormality was found in clinical or experimental conditions [29,55,56,121,122,123,124].