# Ketogenic diet dampens excitatory neurotransmission by shrinking synaptic vesicle pools

## TL;DR

A ketogenic diet changes brain activity by altering gene expression and reducing excitatory signals in the hippocampus, which may explain its benefits in epilepsy and neurodegenerative diseases.

## Contribution

The study reveals that KD causes transcriptional reprogramming in the hippocampus via histone modifications, leading to synaptic adaptations.

## Key findings

- KD induces extensive transcriptional reprogramming, including altered expression of synaptic genes.
- KD reduces excitatory synaptic gain and short-term plasticity at CA3-CA1 synapses.
- Functional changes are driven by a reduction in the readily releasable vesicle pool at excitatory synapses.

## Abstract

Ketogenic diet (KD) is used for the treatment of drug-resistant childhood epilepsy and has been proposed to improve outcomes in neurodegenerative diseases. However, the mechanisms by which KD alters brain circuitry remain unclear. Here, we investigated the impact of KD on hippocampal function through integrative analysis of gene expression and neurotransmission. We found that KD induces extensive transcriptional reprogramming, including altered expression of numerous synaptic genes. Proteomic and genomic profiling revealed significant changes in histone modifications, particularly at promoters of KD-regulated genes. Electrophysiological recordings showed that KD reduces excitatory synaptic gain and short-term plasticity at CA3-CA1 synapses, dampening the summation of excitatory inputs and enhancing the summation of inhibitory inputs. These functional changes were driven, in part, by a reduction in the readily releasable vesicle pool at excitatory synapses under KD. Together, our findings demonstrate that KD drives transcriptional remodeling of hippocampal circuits, leading to synaptic adaptations that may underlie its anti-epileptic and neuroprotective effects.

Stunault et al. show that the ketogenic diet drives extensive transcriptional reprogramming of the hippocampus through histone post-translational modifications, leading to altered short-term plasticity and reduced synaptic integration at the circuit level.