Autism Spectrum Disorder (ASD) is a neurodevelopmental condition defined by persistent differences in social communication and interaction, alongside restricted, repetitive patterns of behavior, interests, or activities. This lifelong condition presents as a spectrum, meaning its manifestations vary significantly among individuals. The pathophysiology of ASD involves the alteration of normal physiological processes caused by the disorder. This complex, multi-faceted process involves biological changes interacting with a genetic predisposition to shape the developing nervous system. ASD is not attributable to a single cause but involves a convergence of changes from the level of DNA to the body’s largest systems.
Genetic Vulnerability and Heritability
ASD possesses high heritability, but it is rarely the result of a single genetic error. The genetic architecture is complex, involving hundreds of genes and two main types of variation. One major component is polygenic risk, which is the cumulative effect of many common genetic variants. Each variant contributes a small amount to the overall risk, establishing a baseline vulnerability.
The second component involves rare, high-impact mutations, which often arise de novo (new in the individual and not inherited). These include Copy Number Variants (CNVs), which are deletions or duplications of large DNA segments, and protein-truncating variants in specific genes. Many genes implicated in these rare mutations play roles in neuronal synaptogenesis, the formation of connections between nerve cells.
Neuroanatomical and Connectivity Differences
The developing brain in ASD often shows structural differences, particularly in volume and growth trajectory. Some individuals exhibit early brain overgrowth, which can lead to macrocephaly (an enlarged head) in the first years of life. This accelerated growth is sometimes observed in the frontal cortex, a region involved in complex cognitive and social behaviors. Changes have also been noted in the amygdala, a structure central to emotion processing and social behavior, including alterations in its size and neuron population.
A central focus of study is the brain’s “connectome,” the map of functional and structural connections between regions. Neuroimaging studies have revealed altered connectivity, suggesting difficulties in integrating information across brain networks. The structural connectome often shows atypical patterns, including reduced global network communication efficiency in regions like the temporal and prefrontal cortices. Atypical structural connectome asymmetry is also observed, particularly in the sensory and default-mode networks, suggesting an imbalance in how the two hemispheres are wired.
Molecular and Synaptic Dysregulation
At the cellular level, communication failure in ASD often stems from synaptic dysfunction, involving problems with nerve cell junctions. This includes issues with the formation, maintenance, and elimination of synapses throughout development. Synaptic pruning, where the brain eliminates unnecessary connections, appears aberrant, potentially leaving too many ineffective synapses. This dysregulation contributes to the hypothesis of an imbalance between excitation and inhibition (E/I) in the brain.
The E/I imbalance refers to a disruption in the ratio between the brain’s main inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), and its main excitatory neurotransmitter, glutamate. Glutamate promotes electrical signaling, while GABA dampens it; stable neural signaling requires a proper balance. Dysfunction of GABAergic interneurons and genetic variations in GABA-system genes are implicated in ASD. An excess of excitatory signaling relative to inhibitory signaling can lead to hyperexcitability, which may underlie symptoms like sensory sensitivities and repetitive behaviors.
Systemic Factors: Immunity and the Gut-Brain Axis
The pathophysiology of ASD extends beyond the central nervous system, involving systemic factors like the immune system and the digestive tract. Within the brain, neuroinflammation is often observed, characterized by the activation of resident immune cells called microglia. Microglia are responsible for immune surveillance and play a role in synaptic pruning. Postmortem studies reveal microglial activation and increased inflammatory mediators, suggesting an ongoing inflammatory process that can impair normal neural circuit development.
This neuroinflammation is linked to the gut-brain axis, a bidirectional communication pathway connecting the digestive system and the brain. Many individuals with ASD experience gastrointestinal issues, often correlating with dysbiosis (altered gut microbiota composition). The gut microbiota influences brain function through microbial byproducts. For example, compounds like lipopolysaccharide (LPS) can be released from the gut, activate peripheral immune pathways, and potentially compromise the blood-brain barrier. This mechanism suggests how gut changes contribute to the neuroinflammation and altered brain function observed in ASD.