The notion of "immune privilege" of the brain has been revised to accommodate its infiltration, at steady state, by immune cells that participate in normal neurophysiology. However, the immune mechanisms that regulate learning and memory remain poorly understood. Here we show that noninflammatory IL-17 derived from a previously unknown foetal-derived meningeal-resident γδ T cell subset promotes cognition. When tested in classical spatial learning paradigms, mice lacking γδ T cells or IL-17 displayed deficient short-term memory, while retaining long-term memory.

Brain-derived neurotrophic factor (BDNF) and its high-affinity full-length (FL) receptor, TrkB-FL, play a central role in the nervous system by providing trophic support to neurons and regulating synaptic plasticity and memory. TrkB and BDNF signaling are impaired in Alzheimer's disease (AD), a neurodegenerative disease involving accumulation of amyloid-β (Aβ) peptide. We recently showed that Aβ leads to a decrease of TrkB-FL receptor and to an increase of truncated TrkB receptors by an unknown mechanism. In the present study, we found that (1) Aβ selectively increases mRNA levels for the truncated TrkB isoforms without affecting TrkB-FL mRNA levels, (2) Aβ induces a calpain-mediated cleavage on TrkB-FL receptors, downstream of Shc-binding site, originating a new truncated TrkB receptor (TrkB-T') and an intracellular fragment (TrkB-ICD), which is also detected in postmortem human brain samples, (3) Aβ impairs BDNF function in a calpain-dependent way, as assessed by the inability of BDNF to modulate neurotransmitter (GABA and glutamate) release from hippocampal nerve terminals, and long-term potentiation in hippocampal slices. It is concluded that Aβ-induced calpain activation leads to TrkB cleavage and impairment of BDNF neuromodulatory actions.

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease commonly diagnosed among the elderly population. AD is characterized by the loss of synaptic connections, neuronal death, and progressive cognitive impairment, attributed to the extracellular accumulation of senile plaques, composed by insoluble aggregates of amyloid-β (Aβ) peptides, and to the intraneuronal formation of neurofibrillary tangles shaped by hyperphosphorylated filaments of the microtubule-associated protein tau. However, evidence showed that chronic inflammatory responses, with long-lasting exacerbated release of proinflammatory cytokines by reactive glial cells, contribute to the pathophysiology of the disease. NLRP3 inflammasome (NLRP3), a cytosolic multiprotein complex sensor of a wide range of stimuli, was implicated in multiple neurological diseases, including AD. Herein, we review the most recent findings regarding the involvement of NLRP3 in the pathogenesis of AD. We address the mechanisms of NLRP3 priming and activation in glial cells by Aβ species and the potential role of neurofibrillary tangles and extracellular vesicles in disease progression. Neuronal death by NLRP3-mediated pyroptosis, driven by the interneuronal tau propagation, is also discussed. We present considerable evidence to claim that NLRP3 inhibition, is undoubtfully a potential therapeutic strategy for AD.

J. Neurochem. (2011) 118, 339–353. Abstract Glycinergic inhibitory transmission has been described in spinal cord, but rather disregarded in the brain. The spatial‐temporal characterization of glycine receptors (GlyR) in the hippocampus over development is herein reported. GlyR expression increases from late embryonic stage (E18) to 7 days postnatal (P7) and decreases from P7 on. Quantitative real‐time PCR showed that GlyR subunit expression changes over neuronal maturation with a preponderance of α2 and α3, over α1 and β. In immature stages, GlyR delineate the cell body of neurons at the Dentate Gyrus and Cornus Ammonis 1 and 3 (CA1/CA3) and are composed of α2 and α3 subunits. At P7, synaptic GlyRα2β can already be observed in the dendritic areas of Dentate Gyrus and of CA1/CA3. In the mature hippocampus, synaptic GlyR decrease and, although a few synaptic GlyRα1β can still be detected in the dendritic layers, extrasynaptic α2/α3‐containing GlyR and somatic localized GlyRα3 are the most abundant. Our results point towards an important function of a slow tonic activation of extrasynaptic GlyR, over a fast phasic activation of synaptic GlyRα1β. We clearly show that GlyR are widely expressed in hippocampus and that their subcellular localization and subunit composition change over development.

Glycine transporters (GlyT), GlyT1 and GlyT2, are responsible for the termination of glycine-mediated synaptic activity through removal of neurotransmitter from synaptic cleft. Brain-derived neurotrophic factor (BDNF) activates its high affinity tropomyosin-related kinase (Trk) receptors, namely TrkB, which includes full length (TrkB-FL) and truncated (TrkB-T) isoforms. In this article we evaluated the influence of BDNF upon the activity of glycine transporters in astrocytes. We report that BDNF decreases GlyT1- and GlyT2- mediated [(3) H]glycine transport in primary cultures of astrocytes from rat cerebral cortex. BDNF decreased Vmax but not Km values of transport, which suggests that BDNF induces transporter internalization. Accordingly, dynasore, an inhibitor of dynamin/clathrin-dependent endocytosis, prevented the influence of BDNF upon GlyT-mediated transport. While quantifying mRNA and protein levels, we detected a predominance of truncated isoforms over the TrkB-FL receptor. The effect of BDNF was not abolished by specific inhibitors of PLCγ, PI3K and MAPK, indicating that it did not occur through TrkB-FL canonical pathways. However, BDNF action was lost in the presence of a Rho family-specific blocker (toxin B), a signaling pathway that has been associated to TrkB-T1. Furthermore, the effect of BDNF was abolished upon TrkB-T knockdown in astrocytes by RNA interference. Immunofluorescence assays confirmed an increased GlyT expression in endosomes upon BDNF incubation, which was prevented in the presence of either dynasore or toxin B. We conclude that BDNF, acting on TrkB-T1 receptors, inhibits glycine uptake in astrocytes by promoting GlyT internalization through a Rho-GTPase activity dependent mechanism.