Tardive dyskinesia is caused by maladaptive synaptic plasticity: a hypothesis

Area of Science:

• Neuroscience
• Movement Disorders
• Neuropharmacology

Background:

• Tardive dyskinesia (TD) has been recognized for 50 years, yet its underlying pathophysiology is incompletely understood.
• Current atypical antipsychotics, while having fewer dopamine receptor interactions, have not eliminated TD, underscoring gaps in knowledge.
• Existing theories on TD pathophysiology require further development to explain the disorder comprehensively.

Purpose of the Study:

• To provide an overview of the current understanding of tardive dyskinesia (TD) pathophysiology.
• To integrate recent advances in genetics and synaptic plasticity research from other hyperkinetic movement disorders.
• To propose a novel hypothesis for TD pathophysiology involving dopamine-receptor sensitization and N-methyl-D-aspartate receptor function.

Main Methods:

• Literature review of existing TD pathophysiology.
• Incorporation of recent genetic findings relevant to movement disorders.
• Analysis of human synaptic plasticity studies in related hyperkinetic conditions.
• Formulation of a testable hypothesis regarding dopamine and NMDA receptor roles.

Main Results:

• The proposed hypothesis integrates dopamine-receptor sensitization and altered N-methyl-D-aspartate receptor function.
• This hypothesis suggests that these neurochemical changes lead to maladaptive synaptic plasticity.
• Maladaptive plasticity is proposed as the mechanism enabling the encoding of abnormal motor programs in TD.

Conclusions:

• The proposed maladaptive synaptic plasticity hypothesis offers a framework to advance TD understanding.
• This hypothesis bridges existing theories of TD with insights from other hyperkinetic movement disorders.
• Further research is needed to experimentally validate or refute the proposed mechanisms.