Maternal n-3 polyunsaturated fatty acids (PUFAs), especially docosahexaenoic acid, is critical during perinatal brain development. How early postnatal n-3 PUFA deficiency impacts on hippocampal synaptic plasticity is mostly unknown. Here we compared activity-dependent plasticity at excitatory and inhibitory synapses in the CA1 region of the hippocampus in weaned pups whose mothers were fed with an n-3 PUFA-balanced or n-3 PUFA-deficient diet. Normally, endogenous cannabinoids (eCB) produced by the post-synapse dually control network activity by mediating the long-term depression of inhibitory inputs (iLTD) and positively gating NMDAR-dependent long-term potentiation (LTP) of excitatory inputs. We found that both iLTD and LTP were impaired in n-3 PUFA-deficient mice. Pharmacological dissection of the underlying mechanism revealed that impairment of NMDAR-dependent LTP was causally linked to and attributable to the ablation of eCB-mediated iLTD and associated to disinhibitory gating of excitatory synapses. The data shed new light on how n-3 PUFAs shape synaptic activity in the hippocampus and provide a new synaptic substrate to the cognitive impairments associated with perinatal n-3 deficiency.

Omega-3 fatty acids (n-3 polyunsaturated fatty acids; n-3 PUFAs) are essential for the functional maturation of the brain. Westernization of dietary habits in both developed and developing countries is accompanied by a progressive reduction in dietary intake of n-3PUFAs. Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental diseases in epidemiological studies, but the mechanisms by which a n-3 PUFA dietary imbalance affects CNS development are poorly understood. Active microglial engulfment of synaptic elements is an important process for normal brain development and altered synapse refinement is a hallmark of several neurodevelopmental disorders. Here, we identify a molecular mechanism for detrimental effects of low maternal n-3 PUFA intake on hippocampal development. Our results show that maternal dietary n-3 PUFA deficiency increases microglial phagocytosis of synaptic elements in the developing hippocampus, through the activation of 12/15-lipoxygenase (LOX)/12-HETE signaling, which alters neuronal morphology and affects cognition in the postnatal offspring. While women of child bearing age are at higher risk of dietary n-3 PUFA deficiency, these findings provide new insights into the mechanisms linking maternal nutrition to neurodevelopmental disorders.One Sentence Summary: Low maternal omega-3 fatty acids intake impairs microgliamediated synaptic refinement via 12-HETE pathway in the developing brain.

Down syndrome (DS), the most common form of intellectual disability, is a chromosomal disorder caused by having all or part of an extra chromosome 21, leading to intellectual disability. Contrary to the extensive research on the Ts65Dn mouse model of DS in the hippocampus, the synaptic foundation of prefrontal cortex (PFC) malfunction in individuals with DS, including working memory deficits, remains largely unclear. A previous study on mBACtgDyrk1a mice, which overexpress theDyrk1agene, showed that this overexpression negatively impacts spine density and synaptic molecular composition, causing synaptic plasticity deficits in the PFC. By comparing Ts65Dn mice, which overexpress multiple genes includingDyrk1a, and mBACtgDyrk1a mice, we aimed to better understand the role of different genes in DS. Results from electrophysiological experiments (i.e., patch-clamp and extracellular field potential recordings ex vivo) in Ts65Dn PFC male mice revealed modifications of intrinsic properties in layer V/VI pyramidal neurons and the synaptic plasticity range. Thus, long-term depression was abolished in Ts65Dn, while synaptic or pharmacological long-term potentiation were fully expressed in Ts65Dn mice. These results, illustrating the phenotypic divergence between the polygenic Ts65Dn model and the monogenic mBACtgDyrk1a model of DS, highlight the complexity of the pathophysiological mechanisms responsible for the neurocognitive symptoms of DS.

The roles played by cortical inhibitory neurons in experience-dependent plasticity are not well understood. Here we evaluate the participation of parvalbumin-expressing (PV+) GABAergic neurons in two forms of experience-dependent modification of primary visual cortex (V1) in adult mice: ocular dominance (OD) plasticity resulting from monocular deprivation and stimulus-selective response potentiation (SRP) resulting from enriched visual experience. These two forms of plasticity are triggered by different events but lead to a similar increase in visual cortical response. Both also require the NMDA class of glutamate receptor (NMDAR). However, we find that PV+ inhibitory neurons in V1 play a critical role in the expression of SRP and its behavioral correlate of familiarity recognition, but not in the expression of OD plasticity. Furthermore, NMDARs expressed within PV+ cells, reversibly inhibited by the psychotomimetic drug ketamine, play a critical role in SRP, but not in the induction or expression of adult OD plasticity.