Which neurotransmitter system abnormality is most consistently implicated in the pathophysiology of Autism Spectrum Disorder?

Explanation

## Neurotransmitter Abnormalities in Autism Spectrum Disorder **Key Point:** The **excitatory-inhibitory (E-I) imbalance hypothesis** is the most robust neurochemical model in ASD. This proposes relative excess of glutamatergic (excitatory) neurotransmission and/or deficiency in GABAergic (inhibitory) neurotransmission, leading to hyperexcitability of neural circuits. ### Neurochemical Models in ASD | Neurotransmitter System | Evidence Level | Role in ASD | |-------------------------|-----------------|-------------| | GABA-Glutamate Imbalance | **High (E-I Hypothesis)** | Glutamate excess / GABA deficiency → neural hyperexcitability, seizures, sensory hypersensitivity | | Serotonin | Moderate | Abnormal levels in some individuals; SSRIs may help with comorbid anxiety/OCD but do not treat core ASD | | Dopamine | Moderate | Implicated in reward processing and social motivation deficits, but not primary | | Acetylcholine | Low | Not a primary focus in ASD pathophysiology | **High-Yield:** The **E-I imbalance hypothesis** explains multiple ASD features: - Seizure risk (30% of ASD have seizures) - Sensory hypersensitivity (hyperexcitability to stimuli) - Restricted repetitive behaviors (rigid neural circuits) - Social communication deficits (abnormal salience processing) **Clinical Pearl:** This hypothesis has led to investigation of GABA-enhancing drugs (e.g., arbaclofen, bumetanide) and glutamate antagonists in ASD trials, though no FDA-approved pharmacotherapy targets the core E-I imbalance yet. **Mnemonic:** **EI = Excitation > Inhibition** in ASD. Remember: GABA = brake pedal (inhibition), Glutamate = gas pedal (excitation). In ASD, the gas is too strong or the brake is too weak.