PR002625 (Project)

Description:Background: Duplications of the human chromosome 15q11-q13 region are among the most prevalent genetic causes of autism spectrum disorder (ASD) and epilepsy. While the genetic link is established, the downstream metabolic consequences, particularly disruptions in neurotransmitter systems, remain poorly characterized. This gap impedes our understanding of the underlying pathophysiology. Objectives: This study aimed to: 1) Quantitatively profile key neurotransmitters in a mouse model of human 15q duplication (orthologous locus on mouse chromosome 7); 2) Compare serum neurotransmitter levels between 15q dup mice and wild-type (WT) controls; and 3) Identify specific neurotransmitter dysregulations linked to this genetic alteration. Key Outcomes: Targeted LC-MS/MS analysis revealed significant disruptions in the dopaminergic and glutamatergic systems. A significant decrease in dopamine levels was observed in 15q dup mice compared to WT controls. Concurrently, a significant increase in glutamate levels was detected. These findings provide direct evidence of a systemic imbalance involving reduced dopaminergic signaling and elevated excitatory glutamate tone in the 15q duplication model. This novel metabolic profile offers a crucial biochemical correlate to the neurological phenotypes and highlights potential therapeutic targets for modulating neurotransmission in related disorders.