Reverse engineering of metabotropic glutamate receptor-dependent long-term depression in the hippocampus

status: publishe

Constitutive hippocampal cholesterol loss underlies poor cognition in old rodents

Cognitive decline is one of the many characteristics of aging. Reduced long-term potentiation (LTP) and long-term depression (LTD) are thought to be responsible for this decline, although the precise mechanisms underlying LTP and LTD dampening in the old remain unclear. We previously showed that aging is accompanied by the loss of cholesterol from the hippocampus, which leads to PI3K/Akt phosphorylation. Given that Akt de-phosphorylation is required for glutamate receptor internalization and LTD, we hypothesized that the decrease in cholesterol in neuronal membranes may contribute to the deficits in LTD typical of aging. Here, we show that cholesterol loss triggers p-Akt accumulation, which in turn perturbs the normal cellular and molecular responses induced by LTD, such as impaired AMPA receptor internalization and its reduced lateral diffusion. Electrophysiology recordings in brain slices of old mice and in anesthetized elderly rats demonstrate that the reduced hippocampal LTD associated with age can be rescued by cholesterol perfusion. Accordingly, cholesterol replenishment in aging animals improves hippocampal-dependent learning and memory in the water maze test.publishedVersionFil: Martín, Mauricio Gerardo. Consejo Superior de Investigaciones Científicas. Centro de Biología Molecular Severo Ochoa; España.Fil: Martín, Mauricio Gerardo. Universidad Autónoma de Madrid. Centro de Biología Molecular Severo Ochoa; España.Fil: Martín, Mauricio Gerardo. Katholieke Universiteit Leuven. Center for Human Genetics. VIB Center for the Biology of Disease; Bélgica.Fil: Ahmed, Tariq. Katholieke Universiteit Leuven. Faculty of Psychology and Educational Sciences. Laboratory of Biological Psychology; Bélgica.Fil: Korovaichuk, Alejandra. Consejo Superior de Investigaciones Científicas. Instituto Cajal. Departamento de Neurobiología Funcional y de Sistemas; España.Fil: Venero, César. Universidad Nacional de Educación a Distancia. Facultad de Psicología. Departamento de Psicobiología; España.Fil: Menchón, Silvia Adriana. Katholieke Universiteit Leuven. Center for Human Genetics. VIB Center for the Biology of Disease; Bélgica.Fil: Menchón, Silvia Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Física Enrique Gaviola; Argentina.Fil: Menchón, Silvia Adriana. Universidad Nacional de Córdoba. Facultad de Matemática, Astronomía y Física; Argentina.Fil: Salas, Isabel. Consejo Superior de Investigaciones Científicas. Centro de Biología Molecular Severo Ochoa; España.Fil: Salas, Isabel. Universidad Autónoma de Madrid. Centro de Biología Molecular Severo Ochoa; España.Fil: Salas, Isabel. Consejo Superior de Investigaciones Científicas. Centro de Biología Molecular Severo Ochoa; España.Fil: Munck, Sebastian. Katholieke Universiteit Leuven. Center for Human Genetics. VIB Center for the Biology of Disease; Bélgica.Fil: Herreras, Oscar. Consejo Superior de Investigaciones Científicas. Instituto Cajal. Departamento de Neurobiología Funcional y de Sistemas; España.Fil: Balschun, Detlef. Katholieke Universiteit Leuven. Faculty of Psychology and Educational Sciences. Laboratory of Biological Psychology; Bélgica.Fil: Dotti, Carlos Gerardo. Consejo Superior de Investigaciones Científicas. Centro de Biología Molecular Severo Ochoa; España.Fil: Dotti, Carlos Gerardo. Universidad Autónoma de Madrid. Centro de Biología Molecular Severo Ochoa; España.Fil: Dotti, Carlos Gerardo. Katholieke Universiteit Leuven. Center for Human Genetics. VIB Center for the Biology of Disease; Bélgica.Biofísic

Neural oscillations during cognitive processes in an <i>App</i> knock-in mouse model of Alzheimer's disease pathology

Multiple animal models have been created to gain insight into Alzheimer's disease (AD) pathology. Among the most commonly used models are transgenic mice overexpressing human amyloid precursor protein (APP) with mutations linked to familial AD, resulting in the formation of amyloid beta plaques, one of the pathological hallmarks observed in AD patients. However, recent evidence suggests that the overexpression of APP by itself can confound some of the reported observations. Therefore, we investigated in the present study the App(NL-G-F)model, an App knock-in (App-KI) mouse model that develops amyloidosis in the absence of APP-overexpression. Our findings at the behavioral, electrophysiological, and histopathological level confirmed an age-dependent increase in A beta 1-42 levels and plaque deposition in these mice in accordance with previous reports. This had apparently no consequences on cognitive performance in a visual discrimination (VD) task, which was largely unaffected in App(NL-G-F) mice at the ages tested. Additionally, we investigated neurophysiological functioning of several brain areas by phase-amplitude coupling (PAC) analysis, a measure associated with adequate cognitive functioning, during the VD task (starting at 4.5 months) and the exploration of home environment (at 5 and 8 months of age). While we did not detect age-dependent changes in PAC during home environment exploration for both the wild-type and the App(NL-G-F) mice, we did observe subtle changes in PAC in the wild-type mice that were not present in the App(NL-G-F) mice

Age Dependency of Infradian Rhythms in Enzymuria of Female Volunteers

Peer Reviewe

Separate ionotropic and metabotropic glutamate receptor functions in depotentiation versus LTP: A distinct role for group1 mGluR subtypes and NMDARs

Depotentiation (DP) is a mechanism by which synapses that have recently undergone long-term potentiation (LTP) can reverse their synaptic strengthening within a short time-window after LTP induction. Group 1 metabotropic glutamate receptors (mGluRs) were shown to be involved in different forms of long-term potentiation and long-term depression, but little is known about their roles in DP. Here, we generated DP by applying low-frequency stimulation (LFS) at 5 Hz after LTP had been induced by a single train of theta-burst-stimulation (TBS). While application of LFS for 2 minutes (DP2') generated only a short-lasting DP that was independent of the activation of NMDA receptors (NMDAR) and group 1 mGluRs, LFS given for 8 min (DP8') induced a robust DP that was maintained for at least two hours. This strong form of DP was contingent on NMDAR activation. Interestingly, DP8' appears to include a metabotropic NMDAR function because it was blocked by the competitive NMDAR antagonist D-AP5 but not by the use-dependent inhibitor MK-801 or high Mg2+. Furthermore, DP8' was enhanced by application of the mGluR1 antagonist (YM 298198, 1μM). The mGluR5 antagonist (MPEP, 40μM), in contrast, failed to affect it. The induction of LTP, in turn, was NMDAR dependent (as tested with D-AP5), and blocked by MPEP but not by YM 298198. These results indicate a functional dissociation of mGluR1 and mGluR5 in two related and consecutively induced types of NMDAR-dependent synaptic plasticity (LTP DP) with far-reaching consequences for their role in plasticity and learning under normal and pathological conditions

Tau- but not Aß -pathology enhances NMDAR-dependent depotentiation in AD-mouse models.

Many mouse models of Alzheimer's disease (AD) exhibit impairments in hippocampal long-term-potentiation (LTP), seemingly corroborating the strong correlation between synaptic loss and cognitive decline reported in human studies. In other AD mouse models LTP is unaffected, but other defects in synaptic plasticity may still be present. We recently reported that THY-Tau22 transgenic mice, that overexpress human Tau protein carrying P301S and G272 V mutations and show normal LTP upon high-frequency-stimulation (HFS), develop severe changes in NMDAR mediated long-term-depression (LTD), the physiological counterpart of LTP. In the present study, we focused on putative effects of AD-related pathologies on depotentiation (DP), another form of synaptic plasticity. Using a novel protocol to induce DP in the CA1-region, we found in 11-15 months old male THY-Tau22 and APPPS1-21 transgenic mice that DP was not deteriorated by Aß pathology while significantly compromised by Tau pathology. Our findings advocate DP as a complementary form of synaptic plasticity that may help in elucidating synaptic pathomechanisms associated with different types of dementia.status: publishe