PPARα deletion induces depressive-like behaviors by impairing neuronal synaptic plasticity and transmission

Emerging evidence highlights the critical role of synaptic transmission and structural remodeling in major depressive disorder (MDD). Recent studies have indicated a strong association between peroxisome proliferator-activated receptors type-α (PPARα) and MDD. In this study, we investigated whether PPARα contributes to MDD by regulating synaptic plasticity. We examined the role of PPARα in neuronal spine morphology, synaptic plasticity and transmission, and depressive-like behaviors in mice lacking PPARα expression. Mice with PPARα gene knockout (PPARα^-/-) exhibited behaviors characteristic of depression. The ablation of PPARα led to a decrease in the expression of synapse-associated proteins and alterations in the morphology and density of dendritic spines in both the hippocampus and prefrontal cortex (PFC). Functionally, PPARα^-/- mice displayed reduced basic synaptic transmission and a significant impairment of long-term potentiation in both hippocampus and PFC. Additionally, there were decrease in N-methyl-D-aspartic acid receptor/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor ratio and miniature excitatory postsynaptic currents in these mice. Overall, the knockout of PPARα profoundly impacts the neuronal structure and function in the hippocampus and PFC, linking these synaptic alterations to depressive-like behaviors. Consequently, PPARα emerges as a vital factor in fundamental neuronal physiology and represents a promising new target for MDD treatment.