Tetraspanin 6: A novel regulator of hippocampal synaptic transmission and long term plasticity

Tetraspanins (Tspan) are transmembrane proteins with important scaffold and signalling functions. Deletions of Tetraspanin 6 (Tspan6) gene, a member of the tetraspanin family, have been reported in patients with Epilepsy Female-restricted with Mental Retardation (EFMR). Interestingly, mutations in Tspan7, highly homologous to Tspan6, are associated with X-linked intellectual disability, suggesting that these two proteins are important for cognition. Considering recent evidences showing that Tspan7 plays a key role in synapse development and AMPAR trafficking, we initiated the study of Tspan6 in synaptic function using a Tspan6 knock out mouse model. Here we report that hippocampal field recordings from Tspan6 knock out mice show an enhanced basal synaptic transmission and impaired long term potentiation (LTP). A normal paired-pulse facilitation response suggests that Tspan6 affects the properties of the postsynaptic rather than the presynaptic terminal. However, no changes in spine morphology or postsynaptic markers could be detected in Tspan6 KO mice compared with wild types. In addition, Tspan6 KO mice show normal locomotor behaviour and no defects in hippocampus-dependent memory tests

Deconstructing holographic liquids

We argue that there exist simple effective field theories describing the long-distance dynamics of holographic liquids. The degrees of freedom responsible for the transport of charge and energy-momentum are Goldstone modes. These modes are coupled to a strongly coupled infrared sector through emergent gauge and gravitational fields. The IR degrees of freedom are described holographically by the near-horizon part of the metric, while the Goldstone bosons are described by a field-theoretical Lagrangian. In the cases where the holographic dual involves a black hole, this picture allows for a direct connection between the holographic prescription where currents live on the boundary, and the membrane paradigm where currents live on the horizon. The zero-temperature sound mode in the D3-D7 system is also re-analyzed and re-interpreted within this formalism.Comment: 21 pages, 2 figure

Molecular and cognitive signatures of ageing partially restored through synthetic delivery of IL2 to the brain

Cognitive decline is a common pathological outcome during aging, with an ill-defined molecular and cellular basis. In recent years, the concept of inflammaging, defined as a low-grade inflammation increasing with age, has emerged. Infiltrating T cells accumulate in the brain with age and may contribute to the amplification of inflammatory cascades and disruptions to the neurogenic niche observed with age. Recently, a small resident population of regulatory T cells has been identified in the brain, and the capacity of IL2-mediated expansion of this population to counter neuroinflammatory disease has been demonstrated. Here, we test a brain-specific IL2 delivery system for the prevention of neurological decline in aging mice. We identify the molecular hallmarks of aging in the brain glial compartments and identify partial restoration of this signature through IL2 treatment. At a behavioral level, brain IL2 delivery prevented the age-induced defect in spatial learning, without improving the general decline in motor skill or arousal. These results identify immune modulation as a potential path to preserving cognitive function for healthy aging.The work was supported by the Wellcome Trust (222442/Z/21/Z to AL), anERC Consolidator Grant TissueTreg (to A.L.), an ERC Proof of Concept GrantTreatBrainDamage (to A.L.), FWO Research Grant1503420N (to E.P.), anSAO-FRA pilot grant (20190032, to E.P.), an ERC Starting Grant AstroFunc(to M.G.H.), ERC Proof of Concept Grant AD-VIP (to M.G.H.), ERA ChairNCBio (to M.G.H.), and the Biotechnology and Biological Sciences ResearchCouncil through Institute Strategic Program Grant funding BBS/E/B/000C0427and BBS/E/B/000C0428, and the Biotechnology and BiologicalSciences Research Council Core Capability Grant to the BabrahamInstitute. E.P. was supported by a fellowship from the FWO. The authorsacknowledge the important contributions of Jeason Haughton (VIB) formouse husbandry, Pier-Andr ee Penttila and the KUL FACS Core, and theVIB Single Cell Sequencing Core. The visual abstract was created with BioRender.com

Increased Insoluble Amyloid-β Induces Negligible Cognitive Deficits in Old AppNL/NL Knock-In Mice

Commonly used Alzheimer's disease mouse models are based on the ectopic overexpression of the human amyloid precursor protein (APP) gene, together with a mutant presenilin gene. Surprisingly, humanized APP knock-in mouse models carrying a single APP Swedish mutation (AppNL), failed to develop amyloid plaque aggregation or cognitive deficits. Here we characterized the effect of this mutation in more advanced ages. We show that 24-month-old AppNL/NL mice, despite presenting an age dependent increase in insoluble amyloid-β oligomers in the prefrontal cortex, they do not develop amyloid plaque deposition, reactive gliosis, or cognitive deficits

A conical deficit in the AdS4/CFT3 correspondence

Inspired by the AdS/CFT correspondence we propose a new duality that allow the study of strongly coupled field theories living in a 2+1 conical space-time. Solving the 4-d Einstein equations in the presence of an infinite static string and negative cosmological constant we obtain a conical AdS4 space-time whose boundary is identified with the 2+1 cone found by Deser, Jackiw and 't Hooft. Using the AdS4/CFT3 correspondence we calculate retarded Green's functions of scalar operators living in the cone.Comment: v3, 14 pages. We reinterpret our results for the Green's functions in the con

Correction: Tetraspanin 6: A novel regulator of hippocampal synaptic transmission and long term plasticity

[This corrects the article DOI: 10.1371/journal.pone.0171968.]

High fat diet treatment impairs hippocampal long-term potentiation without alterations of the core neuropathological features of Alzheimer disease

Type 2 diabetes (T2DM) and obesity might increase the risk for AD by 2-fold. Different attempts to model the effect of diet-induced diabetes on AD pathology in transgenic animal models, resulted in opposite conclusions. Here, we used a novel knock-in mouse model for AD, which, differently from other models, does not overexpress any proteins. Long-term high fat diet treatment triggers a reduction in hippocampal N-acetyl-aspartate/myo-inositol metabolites ratio and impairs long term potentiation in hippocampal acute slices. Interestingly, these alterations do not correlate with changes in the core neuropathological features of AD, i.e. amyloidosis and Tau hyperphosphorylation. The data suggest that AD phenotypes associated with high fat diet treatment seen in other models for AD might be exacerbated because of the overexpressing systems used to study the effects of familial AD mutations. Our work supports the increasing insight that knock-in mice might be more relevant models to study the link between metabolic disorders and AD

Quinolinic acid injection in mouse medial prefrontal cortex affects reversal learning abilities, cortical connectivity and hippocampal synaptic plasticity.

Intracerebral injection of the excitotoxic, endogenous tryptophan metabolite, quinolinic acid (QA), constitutes a chemical model of neurodegenerative brain disease. Complementary techniques were combined to examine the consequences of QA injection into medial prefrontal cortex (mPFC) of C57BL6 mice. In accordance with the NMDAR-mediated synapto- and neurotoxic action of QA, we found an initial increase in excitability and an augmentation of hippocampal long-term potentiation, converting within two weeks into a reduction and impairment, respectively, of these processes. QA-induced mPFC excitotoxicity impaired behavioral flexibility in a reversal variant of the hidden-platform Morris water maze (MWM), whereas regular, extended MWM training was unaffected. QA-induced mPFC damage specifically affected the spatial-cognitive strategies that mice use to locate the platform during reversal learning. These behavioral and cognitive defects coincided with changes in cortical functional connectivity (FC) and hippocampal neuroplasticity. FC between various cortical regions was assessed by resting-state fMRI (rsfMRI) methodology, and mice that had received QA injection into mPFC showed increased FC between various cortical regions. mPFC and hippocampus (HC) are anatomically as well as functionally linked as part of a cortical network that controls higher-order cognitive functions. Together, these observations demonstrate the central functional importance of rodent mPFC as well as the validity of QA-induced mPFC damage as a preclinical rodent model of the early stages of neurodegeneration