Polyunsaturated fatty acids (PUFAs) are essential fatty acids which are provided to the body through the diet. The brain is one of the richest organs in the body and has a high need in PUFAs. There are 2 main families of PUFAs, n-3 (or omega 3) and n-6 (or omega6). While it is quite easy to find n-6 PUFAs in westernized diets, the need in n-3 PUFAs is poorly reached, leading to decreased level of docosahexaenoic acid (DHA) in the brain. In humans, poor levels of blood n-3 PUFAs and brain DHA are associated to a higher prevalence of cognitive disorders and depression. However, the mechanisms underlying the effect of DHA on brain functions are poorly understood. Using mice models of n-3 PUFAs dietary deficiency or supplementation, we revealed that in the brain, DHA regulate neuroinflammatory pathways, in particular through its effect on microglia, the main innate immune system cell in the brain. In addition, n-3 PUFAs are key actors of ndocannabinoid- dependent synaptic plasticity. While neuroinflammation and eCB-dependent synaptic plasticity are crucial to cognition and emotional behaviour alterations, our results bring to the clinical scene the importance of controlling dietary n-3 PUFAs to protect the brain from the adverse effect of stres or inflammation. Altogether, our work brings a better comprehension of how dietary n-3 PUFAs participate to brain physiology and protect from the development of mood and cognitive disorders. It opens new avenues for the use of these lipids in the protection and treatment of brain diseases.

PUFA of the n-3 and n-6 families are present in high concentration in the brain where they are major components of cell membranes. The main forms found in the brain are DHA (22 :6, n-3) and arachidonic acid (20:4, n-6). In the past century, several studies pinpointed that modifications of n-3 and n-6 PUFA levels in the brain through dietary supply or genetic means are linked to the alterations of synaptic function. Yet, synaptopathies emerge as a common characteristic of neurodevelopmental disorders, neuropsychiatric diseases and some neurodegenerative diseases. Understanding the mechanisms of action underlying the activity of PUFA at the level of synapses is thus of high interest. In this frame, dietary supplementation in PUFA aiming at restoring or promoting the optimal function of synapses appears as a promising strategy to treat synaptopathies. This paper reviews the link between dietary PUFA, synapse formation and the role of PUFA and their metabolites in synaptic functions.

Previous microarray analysis of gene expression in frontal cortex showed differential expression of genes associated with synaptic function in schizophrenia compared to matched-controls in two independent cohorts. One of these genes validated in both cohorts, SLC30A3, which encodes the Zinc Transporter 3 (ZNT3), is localised to synaptic vesicles in glutamate synapses and known to be involved in cognitive function. In view of the robust depletion of SLC30A3 mRNA in two independent studies and the importance of this gene in cognitive function, we investigated whether single nucleotide polymorphism (SNP) associations with schizophrenia could be detected in a UK case controlled schizophrenia cohort. Four SNPs were selected across this gene and genotyped in a cohort of cases and controls from East UK. We found significant associations with schizophrenia at the allelic (ORs: 1.51 to 1.57), genotype (ORs: 1.46 to 1.53) and haplotype level (P = 2.15 × 10−4). These associations proved to be gender-specific with significant effects of allele (ORs: 1.74 to 2.11), genotype (ORs: 1.78 to 2.14) and haplotype (P = 3.51 × 10−5) observed in female schizophrenia cases but not males, when split by gender. In conclusion, SNPs in SLC30A3 showed a gender-specific association with schizophrenia in this East UK cohort, which merits further investigation in other population samples.

A growing body of literature has explored the influence of physical activity on brain structure and function. While the mechanisms of this relationship remain largely speculative, recent research suggests that one of the effects of physical exercise is an increase in synaptic long-term potentiation (LTP). This has not yet been explored directly in humans due to the difficulty of measuring LTP non-invasively. However, we have previously established that LTP-like changes in visual-evoked potentials (VEPs) can be measured in humans. Here, we investigated whether physical fitness status affects the degree of visual sensory LTP. Using a self-report measure of physical activity, participants were split into two groups: a high-activity group, and a low-activity group. LTP was measured and compared between the two groups using the previously established electroencephalography-LTP paradigm, which assesses the degree to which the N1b component of the VEP elicited by a sine grating is potentiated (enhanced) following a rapid “tetanic” presentation of that grating. Both groups demonstrated increased negativity in the amplitude of the N1b component of the VEP immediately after presentation of the visual “tetanus,” indicating potentiation. However, after a 30-min rest period, the N1b for the high-activity group remained potentiated while the N1b for the low-activity group returned to baseline. This study presents the first evidence for the impact of self-reported levels of physical activity on LTP in humans, and sheds light on potential neurological mechanisms underlying the relationship between physical fitness and cognition. (JINS, 2015, 21, 831–840)

Maternal dietary Zn deficiency during fetal development induces substantial cognitive dysfunctions in the resultant offspring. The mechanism underlying this effect is unclear. The present study evaluated whether the impairments caused by gestational and lactational Zn deficiency are mediated by the hippocampal calmodulin-dependent protein kinase II α (α-CaMKII)/brain-derived neurotrophic factor (BDNF) signalling pathway as well as whether they can be restored by postnatal Zn supplementation. Rats were randomly divided into four groups on the first day of pregnancy (n 12): control (CO) group; pair-fed (PF) group; Zn-deprived (ZD) group; orally Zn-supplemented group. The spatial memory of the offspring was tested at postnatal day 35 using the Morris water maze. Long-term potentiation (LTP) in the rat hippocampal medial perforant path–dentate gyrus pathway was evaluated simultaneously, and α-CaMKII and BDNF protein levels were examined by Western blot analysis. The results demonstrated that the ZD group exhibited a significantly longer latency period in the Morris water maze as well as a significantly decreased LTP amplitude compared with the CO and PF groups. α-CaMKII and BDNF protein expression in the hippocampus was significantly reduced in the ZD group. Postnatal Zn supplementation restored the cognitive dysfunction induced by gestational Zn deficiency but could not completely reverse the decreased LTP and α-CaMKII/BDNF protein levels. Our findings suggest that the α-CaMKII/BDNF signalling pathway may be involved in Zn deficiency-induced cognitive and synaptic impairments.

Interest in the role of nitric oxide (NO) in the nervous system began with the demonstration that glutamate receptor activation in cerebellar slices causes the formation of a diffusible messenger with properties similar to those of the endothelium-derived relaxing factor. It is now clear that this is due to the Ca2+/calmodulin-dependent activation of the enzyme NO synthase, which forms NO and citrulline from the amino acid L-arginine. The cerebellum has very high levels of NO synthase, and although it has low levels of guanylyl cyclase, cerebellar cyclic guanosine monophosphate (cGMP) levels are an order of magnitude higher than in other brain regions. A transcellular metabolic pathway is also present in the cerebellar cortex to recycle citrulline back to arginine. The NO formed binds to and activates soluble guanylyl cyclase to elevate cGMP levels in target cells. Studies employing NADPH-diaphorase, a selective histochemical marker for NO synthase, together with immunohistochemistry, in situ hybridization and biochemical studies have indicated that NO production occurs in granule and basket cells in the cerebellar cortex, whereas cGMP formation appears to occur largely in other cells, including Purkinje cells. Given that a long-term depression of AMPA currents can be seen in isolated Purkinje cells, this anatomical localization suggests that NO cannot play an essential role in the induction of this form of synaptic plasticity.

In vitro studies using cerebellar slices or cultures, as well as in vivo studies, have demonstrated that NO formation and release occur in the cerebellar cortex in response to NMDA receptor activation. Using intracerebellar microdialysis in awake-behaving animals, we have found that this is associated with a large increase in extracellular cGMP levels in the cerebellar cortex. A similar increase in cGMP efflux is seen in response to activation of AMPA or metabotropic glutamate receptors, or to activation of the climbing fiber input. The increase in extracellular cGMP required the Ca2+-dependent activation of NO synthase, and was potentiated by inhibition of phosphodiesterases or organic anion transport. These results suggest a possible role for cGMP as an intercellular messenger in the cerebellar cortex.

In summary, stimuli that elevate Ca2+ levels in granule or in basket cells will activate NO synthase, which by binding to its receptor-soluble guanylyl cyclase – causes an increase in cGMP. cGMP may then act through protein kinases, phosphodiesterases, and ion channels or receptors to affect cerebellar function.

Cerebellar long-term depression (LTD) is a form of synaptic plasticity, first described by Ito and co-workers, in which simultaneous activation of two excitatory inputs to a Purkinje neuron, parallel fibers (PFs) and climbing fibers (CFs), results in a sustained depression of PF synaptic drive. The purpose of this target article is not to assess the possible role of this synaptic alteration in motor learning, an issue which is addressed by other authors in this volume, nor is it to provide a detailed summary of the work on cerebellar LTD to this point (see Linden & Connor 1993; Crépel et al. 1993 for review) or to place cerebellar LTD within the context of other forms of persistent synaptic depression that occur within the mammalian brain (see Linden 1994b). Rather, it is to discuss results obtained using a very reduced preparation for the study of LTD, embryonic Purkinje neurons grown in culture and stimulated with exogenous excitatory amino acids, and to consider some advantages and limitations of this approach. Recent work using this preparation has suggested that three processes are necessary for the induction of cerebellar LTD: Ca influx through voltage-gated channels, Na influx through AMPA receptor-associated channels or voltage-gated Na channels, and protein kinase C activation - which is dependent upon activation of the metabotropic glutamate receptor mGluRl. In addition, input-specific induction of LTD has been demonstrated in this preparation Under conditions where both spontaneous and evoked neurotransmitter release are reduced or eliminated, indicating that postsynaptic alterations are sufficient to confer this important computational property.

Autism spectrum disorders (ASDs) including classic autism is a group of complex developmental disabilities with core deficits of impaired social interactions, communication difficulties and repetitive behaviors. Although the neurobiology of ASDs has attracted much attention in the last two decades, the role of microglia has been ignored. Existing data are focused on their recognized role in neuroinflammation, which only covers a small part of the pathological repertoire of microglia. This review highlights recent findings on the broader roles of microglia, including their active surveillance of brain microenvironments and regulation of synaptic connectivity, maturation of brain circuitry and neurogenesis. Emerging evidence suggests that microglia respond to pre- and postnatal environmental stimuli through epigenetic interface to change gene expression, thus acting as effectors of experience-dependent synaptic plasticity. Impairments of these microglial functions could substantially contribute to several major etiological factors of autism, such as environmental toxins and cortical underconnectivity. Our recent study on Rett syndrome, a syndromic autistic disorder, provides an example that intrinsic microglial dysfunction due to genetic and epigenetic aberrations could detrimentally affect the developmental trajectory without evoking neuroinflammation. We propose that ASDs provide excellent opportunities to study the influence of microglia on neurodevelopment, and this knowledge could lead to novel therapies.

Broad interest in the rapidly advancing field of microglial involvement in forming neural circuits is evident from the fresh findings published in leading journals. This special issue of Neuron Glia Biology contains a special collection of research articles and reviews concerning the new appreciation of microglial function in the normal physiology of the brain that extends beyond their traditionally understood role in pathology.

Numerous studies have reported an association between cognitive impairment in old age and nutritional factors, including dietary fat. Retinoic acid (RA) plays a central role in the maintenance of cognitive processes via its nuclear receptors (NR), retinoic acid receptor (RAR) and retinoid X receptor (RXR), and the control of target genes, e.g. the synaptic plasticity markers GAP-43/neuromodulin and RC3/neurogranin. Given the relationship between RA and the fatty acid signalling pathways mediated by their respective NR (RAR/RXR and PPAR), we investigated the effect of a high-fat diet (HFD) on (1) PUFA status in the plasma and brain, and (2) the expression of RA and fatty acid NR (RARβ, RXRβγ and PPARδ), and synaptic plasticity genes (GAP-43 and RC3), in young male Wistar rats. In the striatum of rats given a HFD for 8 weeks, real-time PCR (RT-PCR) revealed a decrease in mRNA levels of RARβ ( − 14 %) and PPARδ ( − 13 %) along with an increase in RXRβγ (+52 %). Concomitantly, RT-PCR and Western blot analysis revealed (1) a clear reduction in striatal mRNA and protein levels of RC3 ( − 24 and − 26 %, respectively) and GAP-43 ( − 10 and − 42 %, respectively), which was confirmed by in situ hybridisation, and (2) decreased hippocampal RC3 and GAP-43 protein levels (approximately 25 %). Additionally, HFD rats exhibited a significant decrease in plasma ( − 59 %) and brain ( − 6 %) n-3 PUFA content, mainly due to the loss of DHA. These results suggest that dietary fat induces neurobiological alterations by modulating the brain RA signalling pathway and n-3 PUFA content, which have been previously correlated with cognitive impairment.

Horizontal cells of the carp retina alter their synaptic connections with cones during dark and light adaptation. At light onset, dendrites of horizontal cells, which are positioned laterally at the ribbon synapse, form “spinules,” little processes with membrane densities. Spinules are retracted again during dark adaptation. Spinule retraction is also elicited upon glutamate application to the retina. In the present study, we address the question whether calcium/calmodulin-dependent pathways are involved in dark- and glutamate-evoked spinule retraction. Light-adapted retinas were isolated and subsequently dark adapted during incubation in media of different calcium concentrations. Spinule retraction was clearly blocked in low-calcium solutions (5 μM and 50 nM CaCl2). Incubation in medium containing cobalt chloride (2 mM) had the same effect. Both treatments blocked the glutamate-induced spinule retraction as well. These results indicate that spinule retraction is induced by a calcium influx into horizontal cells. To investigate whether calmodulin, the primary calcium receptor in eukaryotic cells, is present at the site of spinule formation, light- and dark-adapted retinas, embedded in LR White resin, were labelled with an antibody against calmodulin and gold-conjugated secondary antibodies. Horizontal cell dendrites at the ribbon synapse revealed strong calmodulin immunoreactivity, which was more than twice as high in light- as in dark-adapted retinas. The incubation of isolated retinas with the calmodulin antagonists W5 and W13 inhibited spinule retraction. In summary, these results suggest that spinule retraction may be regulated by calcium influx into horizontal cells and subsequent calcium/calmodulin-dependent pathways.

During the light phase of a light/dark cycle, dendrites of teleost cone horizontal cells display numerous finger-like projections, called spinules, which are formed at dawn and degraded at dusk, and are thought to be involved in chromatic feedback processes. We have studied the oscillations of these spinules during a normal light/dark cycle and during 48 h of constant darkness in two groups of strongly rhythmic, diurnal fish, Aequidens pulcher. In one group the retinal dopaminergic system had been destroyed by the application of 6-OHDA, while in the other (control) group, the dopaminergic system was intact. In control fish, oscillations of spinule numbers were observed under both normal and constant dark conditions, indicating the presence of a robust circadian rhythm. However, spinule dynamics were severely affected by the absence of retinal dopamine. During the normal light phase, the number of spinules in 6-OHDA injected retinae was strongly reduced, and throughout continual darkness, spinule formation was almost completely suppressed. These results indicate that dopamine is essential for both light-evoked and circadian spinule formation; furthermore, we conclude that there is no circadian oscillator within horizontal cells controlling the formation of spinules.

Investigations examining the role of polysialic acid (PSA) on the neural cell adhesion molecule (NCAM) in synaptic plasticity have yielded inconsistent data. Here, we addressed this issue by determining whether homosynaptic long-term potentiation (LTP) and heterosynaptic long-term depression (LTD) induce changes in the distribution of PSA-NCAM in the dentate gyrus (DG) of rats in vivo. In addition, we also examined whether the observed modifications were initiated via the activation of N-methyl-d-aspartate (NMDA) receptors. Immunocytochemical analysis showed an increase in PSA-NCAM positive cells both at 2 and 24 h following high-frequency stimulation of either medial or lateral perforant paths, leading to homosynaptic LTP and heterosynaptic LTD, respectively, in the medial molecular layer of the DG. Analysis of sub-cellular distribution of PSA-NCAM by electron microscopy showed decreased PSA dendritic labelling in LTD rats and a sub-cellular relocation towards the spines in LTP rats. Importantly, these modifications were found to be independent of the activation of NMDA receptors. Our findings suggest that strong activation of the granule cells up-regulates PSA-NCAM synthesis which then incorporates into activated synapses, representing NMDA-independent plastic processes that act synergistically on LTP/LTD mechanisms without participating in their expression.