Omega-3 fatty acids regulate plasticity in distinct hippocampal glutamatergic synapses.

Dietary omega-3 fatty acids accumulate and are actively retained in central nervous system membranes, mainly in synapses, dendrites and photoreceptors. Despite this selective enrichment, their impact on synaptic function and plasticity has not been fully determined at the molecular level. In this study, we explored the impact of omega-3 fatty acid deficiency on synaptic function in the hippocampus. Dietary omega-3 fatty acid deficiency for 5 months after weaning led to a 65% reduction in the concentration of docosahexaenoic acid in whole brain synaptosomal phospholipids with no impact on global dopaminergic or serotonergic turnover. We observed reduced concentrations of glutamate receptor subunits, including GluA1, GluA2 and NR2B, and synaptic vesicle proteins synaptophysin and synaptotagmin 1 in hippocampal synaptosomes of omega-3 fatty acid-deficient mice as compared to the omega-3 fatty acid rich group. In contrast, an increased concentration of neuronal inositol 1,4,5-trisphosphate-receptor (IP3 -R) was observed in the deficient group. Furthermore, omega-3 fatty acid deficiency reduced the long-term potentiation (LTP) in stratum oriens of the hippocampal CA1 area, but not in stratum radiatum. Thus, omega-3 fatty acids seem to have specific effects in distinct subsets of glutamatergic synapses, suggesting specific molecular interactions in addition to altering plasma membrane properties on a more global scale.

Altered α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor function and expression in hippocampus in a rat model of attention-deficit/hyperactivity disorder (ADHD).

Glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) carry the bulk of excitatory synaptic transmission. Their modulation plays key roles in synaptic plasticity, which underlies hippocampal learning and memory. A dysfunctional glutamatergic system may negatively affect learning abilities and underlie symptoms of attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to investigate whether the expression and function of AMPARs were altered in ADHD. We recorded AMPAR mediated synaptic transmission at hippocampal excitatory synapses and quantified immunogold labelling density of AMPAR subunits GluA1 and GluA2/3 in a rat model for ADHD; the spontaneously hypertensive rat (SHR). Electrophysiological recordings showed significantly reduced AMPAR mediated synaptic transmission at the CA3-to-CA1 pyramidal cell synapses in stratum radiatum and stratum oriens in SHRs compared to control rats. Electronmicroscopic immunogold quantifications did not show any statistically significant changes in labelling densities of the GluA1 subunit of the AMPAR on dendritic spines in stratum radiatum or in stratum oriens. However, there was a significant increase of the GluA2/3 subunit intracellularly in stratum oriens in SHR compared to control, interpreted as a compensatory effect. The proportion of synapses lacking AMPAR subunit labelling was the same in the two genotypes. In addition, electronmicroscopic examination of tissue morphology showed the density of this type of synapse (i.e., asymmetric synapses on spines), and the average size of the synaptic membranes, to be the same. AMPAR dysfunction, possibly involving molecular changes, in hippocampus may in part reflect altered learning in individuals with ADHD.

Presynaptic increase in IP3 receptor type 1 concentration in the early phase of hippocampal synaptic plasticity.

The inositol 1,4,5-trisphosphate receptor (IP3R) subtype IP3R1 is highly enriched in the brain, including hippocampal neurons. It plays an important function in regulating intracellular calcium concentrations. Residing on the smooth endoplasmic reticulum (sER), the IP3R1 mobilizes calcium into the cytosol upon binding the intracellular signaling molecule IP3, whose concentration is increased by stimulating certain metabotropic glutamate receptors. Increased calcium may mediate synaptic changes occurring during long-term plasticity, which includes molecular mechanisms underlying memory encoding. The exact synaptic localization of IP3R1 in the central nervous system (CNS) remains unclear. We hypothesized that IP3R1, in addition to its known expression in soma and dendritic shafts of hippocampal CA1 pyramidal neurons, also may be present in postsynaptic spines. Moreover, we hypothesized that IP3R1 may be present in presynaptic terminals as well, given the importance of calcium in regulating presynaptic neurotransmitter exocytosis. To test these two hypotheses, we used IP3R1 immunocytochemistry at the light and electron microscopical levels in the CA1 area of the hippocampus. Furthermore, we hypothesized that induction of long-term potentiation (LTP) would be accompanied by an increase in synaptic IP3R1 concentrations, thereby facilitating synaptic mechanisms of long term plasticity. To investigate this, we used quantitative immunogold electron microscopy to determine possible changes in IP3R1 concentration in sub-synaptic compartments before and five minutes after high frequency tetanizations. Firstly, our data confirm localization of IP3R1 in both presynaptic terminals and postsynaptic spines. Secondly, the concentration of IP3R1 after tetanization was significantly increased in the presynaptic compartment, suggesting a presynaptic role of IP3R1 in early phases of synaptic plasticity. It is therefore possible that IP3R1 is involved in modulating neurotransmitter release by regulating calcium homeostasis presynaptically.