The corollaries of the obesity epidemic that plagues developed societies are malnutrition and resulting biochemical imbalances. Low levels of essential n-3 polyunsaturated fatty acids (n-3 PUFAs) have been linked to neuropsychiatric diseases, but the underlying synaptic alterations are mostly unknown. We found that lifelong n-3 PUFAs dietary insufficiency specifically ablates long-term synaptic depression mediated by endocannabinoids in the prelimbic prefrontal cortex and accumbens. In n-3-deficient mice, presynaptic cannabinoid CB(1) receptors (CB(1)Rs) normally responding to endocannabinoids were uncoupled from their effector G(i/o) proteins. Finally, the dietary-induced reduction of CB(1)R functions in mood-controlling structures was associated with impaired emotional behavior. These findings identify a plausible synaptic substrate for the behavioral alterations caused by the n-3 PUFAs deficiency that is often observed in western diets.

The mechanisms governing the recruitment of functional glutamate receptors at nascent excitatory postsynapses following initial axondendrite contact remain unclear. We examined here the ability of neurexin/neuroligin adhesions to mobilize AMPA-type glutamate receptors (AMPARs) at postsynapses through a diffusion/trap process involving the scaffold molecule PSD-95. Using single nanoparticle tracking in primary rat and mouse hippocampal neurons overexpressing or lacking neuroligin-1 (Nlg1), a striking inverse correlation was found between AMPAR diffusion and Nlg1 expression level. The use of Nlg1 mutants and inhibitory RNAs against PSD-95 demonstrated that this effect depended on intact Nlg1/PSD-95 interactions. Furthermore, functional AMPARs were recruited within 1 h at nascent Nlg1/PSD-95 clusters assembled by neurexin-1␤ multimers, a process requiring AMPAR membrane diffusion. Triggering novel neurexin/neuroligin adhesions also caused a depletion of PSD-95 from native synapses and a drop in AMPAR miniature EPSCs, indicating a competitive mechanism. Finally, both AMPAR level at synapses and AMPAR-dependent synaptic transmission were diminished in hippocampal slices from newborn Nlg1 knock-out mice, confirming an important role of Nlg1 in driving AMPARs to nascent synapses. Together, these data reveal a mechanism by which membrane-diffusing AMPARs can be rapidly trapped at PSD-95 scaffolds assembled at nascent neurexin/neuroligin adhesions, in competition with existing synapses.

Metabotropic glutamate receptor subtype 5 (mGluR5) is crucially implicated in the pathophysiology of Fragile X Syndrome (FXS); however, its dysfunction at the sub-cellular level, and related synaptic and cognitive phenotypes are unexplored. Here, we probed the consequences of mGluR5/Homer scaffold disruption for mGluR5 cell-surface mobility, synaptic N-methyl-D-aspartate receptor (NMDAR) function, and behavioral phenotypes in the second-generation Fmr1 knockout (KO) mouse. Using single-molecule tracking, we found that mGluR5 was significantly more mobile at synapses in hippocampal Fmr1 KO neurons, causing an increased synaptic surface co-clustering of mGluR5 and NMDAR. This correlated with a reduced amplitude of synaptic NMDAR currents, a lack of their mGluR5-activated long-term depression, and NMDAR/hippocampus dependent cognitive deficits. These synaptic and behavioral phenomena were reversed by knocking down Homer1a in Fmr1 KO mice. Our study provides a mechanistic link between changes of mGluR5 dynamics and pathological phenotypes of FXS, unveiling novel targets for mGluR5-based therapeutics.

Recent evidence suggests that interleukin-1β (IL-1β), which was originally identified as a proinflammatory cytokine, is also required in the brain for memory processes. We have previously shown that IL-1β synthesis in the hippocampus is dependent on P2X7 receptor (P2X7R), which is an ionotropic receptor of ATP. To substantiate the role of P2X7R in both brain IL-1β expression and memory processes, we examined the induction of IL-1β mRNA expression in the hippocampus of wild-type (WT) and homozygous P2X7 receptor knockout mice (P2X7R−/−) following a spatial memory task. The spatial recognition task induced both IL-1β mRNA expression and c-Fos protein activation in the hippocampus of WT but not of P2X7R−/− mice. Remarkably, P2X7R−/− mice displayed spatial memory impairment in a hippocampal-dependant task, while their performances in an object recognition task were unaltered. Taken together, our results show that P2X7R plays a critical role in spatial memory processes and the associated hippocampal IL-1β mRNA synthesis and c-Fos activation.

The grik2 gene, coding for the kainate receptor subunit GluK2 (formerly GluR6), is associated with autism spectrum disorders and intellectual disability. Here, we tested the hypothesis that GluK2 could play a role in the appropriate maturation of synaptic circuits involved in learning and memory. We show that both the functional and morphological maturation of hippocampal mossy fiber to CA3 pyramidal cell (mf-CA3) synapses is delayed in mice deficient for the GluK2 subunit (GluK2 Ϫ/Ϫ ). In GluK2 Ϫ/Ϫ mice this deficit is manifested by a transient reduction in the amplitude of AMPA-EPSCs at a critical time point of postnatal development, whereas the NMDA component is spared. By combining multiple probability peak fluctuation analysis and immunohistochemistry, we have provided evidence that the decreased amplitude reflects a decrease in the quantal size per mf-CA3 synapse and in the number of active synaptic sites. Furthermore, we analyzed the time course of structural maturation of CA3 synapses by confocal imaging of YFP-expressing cells followed by tridimensional (3D) anatomical reconstruction of thorny excrescences and presynaptic boutons. We show that major changes in synaptic structures occur subsequently to the sharp increase in synaptic transmission, and more importantly that the course of structural maturation of synaptic elements is impaired in GluK2 Ϫ/Ϫ mice. This study highlights how a mutation in a gene linked to intellectual disability in the human may lead to a transient reduction of synaptic strength during postnatal development, impacting on the proper formation of neural circuits linked to memory.

Maternal immune activation (MIA) is a common environmental insult on the developing brain and represents a risk factor for neurodevelopmental disorders. Animal models of in utero inflammation further revealed a causal link between maternal inflammatory activation during pregnancy and behavioural impairment relevant to neurodevelopmental disorders in the offspring. Accumulating evidence point out that proinflammatory cytokines produced both in the maternal and fetal compartments are responsible for social, cognitive and emotional behavioral deficits in the offspring. Polyunsaturated fatty acids (PUFAs) are essential fatty acids with potent immunomodulatory activities. PUFAs and their bioactive derivatives can promote or inhibit many aspects of the immune and inflammatory response. PUFAs of the n-3 series ('n-3 PUFAs', also known as omega-3) exhibit anti-inflammatory/pro-resolution properties and promote immune functions, while PUFAs of the n-6 series ('n-6 PUFAs' or omega-6) favor pro-inflammatory responses. The present study aimed at providing insight into the effects of n-3 PUFAs on the consequences of MIA on brain development. We hypothesized that a reduction in n-3 PUFAs exacerbates both maternal and fetal inflammatory responses to MIA and later-life defects in memory in the offspring. Based on a lipopolysaccharide (LPS) model of MIA (LPS injection at embryonic day 17), we showed that n-3 PUFA deficiency 1) alters fatty acid composition of the fetal and adult offspring brain; 2) exacerbates maternal and fetal inflammatory processes with no significant alteration of microglia phenotype, and 3) induces spatial memory deficits in the adult offspring. We also showed a strong negative correlation between brain content in n-3 PUFA and cytokine production in MIA-exposed fetuses. Overall, our study is the first to address the deleterious effects of n-3 PUFA deficiency on brain lipid composition, inflammation and memory performances in MIA-exposed animals and indicates that it should be considered as a potent environmental risk factor for the apparition of neurodevelopmental disorders.

Early Alzheimer's disease (AD) affects the brain non-uniformly, causing hippocampal memory deficits long before widespread brain degeneration becomes evident. Here we addressed whether mossy fiber inputs from the dentate gyrus onto CA3 principal cells are affected in an AD mouse model before amyloid ␤ plaque deposition. We recorded from CA3 pyramidal cells in a slice preparation from 6-month-old male APP/PS1 mice, and studied synaptic properties and intrinsic excitability. In parallel we performed a morphometric analysis of mossy fiber synapses following viral based labeling and 3D-reconstruction. We found that the basal structural and functional properties as well as presynaptic short-term plasticity at mossy fiber synapses are unaltered at 6 months in APP/PS1 mice. However, transient potentiation of synaptic transmission mediated by activity-dependent release of lipids was abolished. Whereas the presynaptic form of mossy fiber long-term potentiation (LTP) was not affected, the postsynaptic LTP of NMDAR-EPSCs was reduced. In addition, we also report an impairment in feedforward inhibition in CA3 pyramidal cells. This study, together with our previous work describing deficits at CA3-CA3 synapses, provides evidence that early AD affects synapses in a projection-dependent manner at the level of a single neuronal population.

Distinct subtypes of ionotropic glutamate receptors can segregate to specific synaptic inputs in a given neuron. Using functional mapping by focal glutamate uncaging in CA3 pyramidal cells (PCs), we observe that kainate receptors (KARs) are strictly confined to the postsynaptic elements of mossy fibre (mf) synapses and excluded from other glutamatergic inputs and from extrasynaptic compartments. By molecular replacement in organotypic slices from GluK2 knockout mice, we show that the faithful rescue of KAR segregation at mf-CA3 synapses critically depends on the amount of GluK2a cDNA transfected and on a sequence in the GluK2a C-terminal domain responsible for interaction with N-cadherin. Targeted deletion of N-cadherin in CA3 PCs greatly reduces KAR content in thorny excrescences and KAR-EPSCs at mf-CA3 synapses. Hence, multiple mechanisms combine to confine KARs at mf-CA3 synapses, including a stringent control of the amount of GluK2 subunit in CA3 PCs and the recruitment/stabilization of KARs by N-cadherins.