MATERNAL HIGH-FAT DIET DISRUPTS INHIBITORY SYNAPTIC PLASTICITY IN THE OFFSPRING HIPPOCAMPUS VIA ENDOCANNABINOID SIGNALING

Maternal exposure to a high-fat diet (mHFD) is associated with cognitive deficits in offspring, along with molecular and structural changes in the hippocampus. However, the synaptic mechanisms linking early-life metabolic environment to long-term hippocampal dysfunction are not fully understood. Here, we aimed to investigate whether mHFD alters inhibitory synaptic transmission and plasticity in the juvenile hippocampus, potentially contributing to cognitive deficits.
Female mice were fed a high-fat diet (60% kcal from fat) starting one month before mating and continuing through gestation and lactation. Whole-cell electrophysiological recordings were performed in acute hippocampal slices from juvenile offspring (postnatal days 30–45) to assess activity-dependent inhibitory synaptic function in CA1 pyramidal neurons.
Consistent with our previous reports, offspring from mHFD dams showed increased inhibitory synaptic efficacy. Importantly, we identified a previously unreported form of inhibitory long-term depression (I-LTD) mediated by endocannabinoid signaling, indicating a reorganization of inhibitory synaptic plasticity. These changes in inhibitory plasticity may underlie the cognitive deficits observed in juvenile offspring from mHFD dams.
Overall, our results demonstrate that maternal high-fat diet exposure leads to enduring alterations in hippocampal inhibitory plasticity. The emergence of abnormal endocannabinoid-dependent I-LTD reflects a maladaptive shift in mechanisms that normally maintain excitatory–inhibitory balance, providing new insight into how early-life obesogenic environments shape synaptic function and cognitive vulnerability.