Ketogenic diet dampens excitatory neurotransmission by shrinking synaptic vesicle pools

The ketogenic diet (KD) is a common dietary intervention for treating seizures in intractable childhood epilepsies and has been proposed to improve disease outcome in neurodegenerative disorders. Despite its clinical applications, we know little about how this diet impacts brain circuitry and neuronal function to elicit its protective effects. Here, we examined the impact of the KD on hippocampal function through integrative analysis of gene expression, epigenetics and neurotransmission. We found that KD induces profound transcriptional reprogramming of the hippocampus, including altered expression of numerous synaptic genes. Proteomic analysis of histone variants and post-translational modifications also revealed significant changes in activating and repressive epigenetic marks in the hippocampus of KD mice. To determine how transcriptional and epigenetic rewiring of the hippocampus under KD impacts neurotransmission, we performed electrophysiological recordings to examine synaptic dynamics and synaptic summation at CA3-CA1 synapses. We found that KD diminishes synaptic gain and dampens short-term plasticity at excitatory synapses, resulting in reduced summation of synaptic inputs at the circuit level. We determined that the dampening of synaptic gain was due to a reduction in size of the readily releasable as well as the total of synaptic vesicles in excitatory but not inhibitory synapses. Our findings show that the ketogenic diet triggers synaptic remodeling in the hippocampus, driven by broad transcriptional and epigenetic changes that reduce synaptic vesicle pools and short-term plasticity at excitatory synapses ultimately dampening excitatory synaptic gain and integration at the circuit level. These synaptic adaptations may represent a major mechanism underlying the anti-epileptic effects of this diet.