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 dampened expression of numerous synaptic genes.
Through proteomic analysis of histone variants and post-translational
modifications, we uncovered significant changes in activating and
repressive histone marks in the hippocampus of KD mice. To determine how
transcriptional rewiring of the hippocampus under KD impacts
neurotransmission, we performed electrophysiological recordings of
neurotransmission and synaptic dynamics at excitatory CA3-CA1 synapses. We
found that KD diminishes synaptic gain and dampens short-term plasticity
at excitatory synapses, resulting in reduced integration of synaptic
inputs at the circuit level. Combining electrophysiology and electron
microscopy, we determined that effects of KD in excitatory synapses are
caused by a reduction in size of the readily releasable pool of synaptic
vesicles, as well as the total vesicle pool. 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.