METABOLISM, REDOX BALANCE AND BEHAVIOR OF TRAP1 MUTANT MICE - A NEW MITOCHONDRIA-LINKED MODEL OF ASD

Neuronal cells critically depend on mitochondrial activity to maintain membrane excitability, neurotransmission, and synaptic plasticity. Accordingly, mitochondrial dysfunction has been observed in autism spectrum disorders (ASD), although the causal relationships remain unclear. In an individual with ASD whose identical twin was unaffected, we identified a mutation (p.Q639*) in the Trap1 gene. TRAP1 is a mitochondrial chaperone belonging to the HSP90 family and plays a key role in regulating cellular metabolism and protecting against oxidative stress. To investigate the functional consequences of TRAP1 loss in vivo, we generated knock-in Trap1 p.Q641* mice. These mice display social behavior deficits, which are more pronounced in males.

We next performed a comprehensive behavioral assessment of Trap1 mutant mice of both sexes. Across a battery of behavioral tests, mutant mice did not exhibit overt phenotypic differences compared to wild-type controls, apart from differences in adaptation to new environment and previously described social deficits. To investigate whether TRAP1 deficiency affects brain metabolism, we performed mass spectrometry–based proteomic analyses of two brain regions frequently affected in ASD, the prefrontal cortex and hippocampus. These analyses revealed sex-dependent effects of the Trap1 mutation on protein expression profiles, pointing to alterations in metabolic pathways in the brain. Given the central role of mitochondria in metabolic regulation, we further assessed redox balance, a key indicator of mitochondrial function and metabolic state. Together, these data indicate that TRAP1 deficiency leads to metabolic alterations in the prefrontal cortex and hippocampus in a sex-specific manner in this genetic mouse model of ASD.