Acsl4-mediated Lipid Homeostasis Orchestrates Synaptic and Cognitive Plasticity

Intellectual disability (ID) affects 1–3% of the population, yet effective therapies remain elusive. Dysregulated lipid metabolism has been implicated in ID, but the underlying mechanisms and translational potential are poorly understood. Here, we identify the lipid-metabolizing enzyme acyl-coenzyme A (CoA) synthetase long-chain family member 4 (Acsl4) as a key regulator of synaptic plasticity, engram cell activation, and cognition, in a developmental stage-dependent manner. Neuron-specific Acsl4 knockout mice, which recapitulate key features of human ID, exhibit disrupted diacylglycerol-protein kinase c (PKC) signaling – a pathway essential for memory formation. Lipidomic and transcriptomic profiling reveals a reduction in diacylglycerol species and downregulation of synapse-related genes. Remarkably, restoring expression of the brain-specific Acsl4_B isoform via AAV-mediated gene therapy during development, or pharmacologically activating PKC with Bryostatin 1 – a clinically tested compound – fully rescues cognitive and synaptic deficits. These findings define the pathogenic mechanism of ACSL4-related ID and uncover a therapeutically actionable lipid signaling pathway, providing a framework for targeted intervention in neurodevelopmental disorders involving lipid dysregulation.