DM1 Transgenic Mice Exhibit Abnormal Neurotransmitter Homeostasis and Synaptic Plasticity in Association with RNA Foci and Mis-Splicing in the Hippocampus.

Myotonic dystrophy type 1 (DM1) is a severe neuromuscular disease mediated by a toxic gain of function of mutant RNAs. The neuropsychological manifestations affect multiple domains of cognition and behavior, but their etiology remains elusive. Transgenic DMSXL mice carry the DM1 mutation, show behavioral abnormalities, and express low levels of GLT1, a critical regulator of glutamate concentration in the synaptic cleft.

P2X7-deficiency improves plasticity and cognitive abilities in a mouse model of Tauopathy.

Alzheimer's disease is the most common form of dementia characterized by intracellular aggregates of hyperphosphorylated Tau protein and extracellular accumulation of amyloid β (Aβ) peptides. We previously demonstrated that the purinergic receptor P2X7 (P2X7) plays a major role in Aβ-mediated neurodegeneration but the relationship between P2X7 and Tau remained overlooked. Such a link was supported by cortical upregulation of P2X7 in patients with various type of frontotemporal lobar degeneration, including mutation in the Tau-coding gene, MAPT, as well as in the brain of a Tauopathy mouse model (THY-Tau22).

Citrulline prevents age-related LTP decline in old rats.

The prevalence of cognitive decline is increasing as the ageing population is considerably growing. Restricting this age-associated process has become a challenging public health issue. The age-related increase in oxidative stress plays a major role in cognitive decline, because of its harmful effect on functional plasticity of the brain, such as long-term potentiation (LTP).

LSP5-2157 a new inhibitor of vesicular glutamate transporters.

Vesicular glutamate transporters (VGLUT1-3) mediate the uptake of glutamate into synaptic vesicles. VGLUTs are pivotal actors of excitatory transmission and of almost all brain functions. Their implication in various pathologies has been clearly documented.

GLS1 Mutant Mice Display Moderate Alterations of Hippocampal Glutamatergic Neurotransmission Associated with Specific Adaptive Behavioral Changes.

Significant alterations in glutamatergic neurotransmission have been reported in major depressive disorder (MDD) that could underlie psychiatric traits. Studies were mainly interested in synaptic dysfunction in the prefrontal cortex, a key structure involved in depressive-like behavior, however hippocampus has been shown to be important in MDD. As cognitive deficits such as hippocampus-memory process were observed in MDD, we investigated in a mild hypoglutamatergic model behaviors related to depression and memory, synaptic transmission parameters and glutamatergic state specifically in the hippocampus.

Susceptibility to Aβo and TBOA of LTD and Extrasynaptic NMDAR-Dependent Tonic Current in the Aged Rat Hippocampus.

Aging, as the major risk factor of Alzheimer's disease (AD), may increase susceptibility to neurodegenerative diseases through many gradual molecular and biochemical changes. Extracellular glutamate homeostasis and extrasynaptic glutamate N-methyl-D-aspartate receptors (NMDAR) are among early synaptic targets of oligomeric amyloid β (Aβo), one of the AD related synaptotoxic protein species. In this study, we asked for the effects of Aβo on long-term depression (LTD), a form of synaptic plasticity dependent on extrasynaptic NMDAR activation, and on a tonic current (TC) resulting from the activation of extrasynaptic NMDAR by ambient glutamate in hippocampal slices from young (3-6-month-old) and aged (24-28-month-old) Sprague-Dawley rats.

Reinstating plasticity and memory in a tauopathy mouse model with an acetyltransferase activator.

Chromatin acetylation, a critical regulator of synaptic plasticity and memory processes, is thought to be altered in neurodegenerative diseases. Here, we demonstrate that spatial memory and plasticity (LTD, dendritic spine formation) deficits can be restored in a mouse model of tauopathy following treatment with CSP-TTK21, a small-molecule activator of CBP/p300 histone acetyltransferases (HAT). At the transcriptional level, CSP-TTK21 re-established half of the hippocampal transcriptome in learning mice, likely through increased expression of neuronal activity genes and memory enhancers.

Evidence for altered dendritic spine compartmentalization in Alzheimer's disease and functional effects in a mouse model.

Alzheimer's disease (AD) is associated with a progressive loss of synapses and neurons. Studies in animal models indicate that morphological alterations of dendritic spines precede synapse loss, increasing the proportion of large and short ("stubby") spines. Whether similar alterations occur in human patients, and what their functional consequences could be, is not known.

βAPP Processing Drives Gradual Tau Pathology in an Age-Dependent Amyloid Rat Model of Alzheimer's Disease.

The treatment of Alzheimer's disease (AD) remains challenging and requires a better in depth understanding of AD progression. Particularly, the link between amyloid protein precursor (APP) processing and Tau pathology development remains poorly understood. Growing evidences suggest that APP processing and amyloid-β (Aβ) release are upstream of Tau pathology but the lack of animal models mimicking the slow progression of human AD raised questions around this mechanism.

GABAergic Microcircuits in Alzheimer's Disease Models.

Background: The early phase of Alzheimer`s disease (AD) involves the disruption of finely tuned neuronal circuitry in brain regions associated with learning and memory. This tuning is obtained from the delicate balance of excitatory and inhibitory inputs which regulate cortical network function. This homeostatic plasticity provides a dynamic basis for appropriate information transfer in the brain.

Alzheimer's disease-like APP processing in wild-type mice identifies synaptic defects as initial steps of disease progression.

Background: Alzheimer's disease (AD) is the most frequent form of dementia in the elderly and no effective treatment is currently available. The mechanisms triggering AD onset and progression are still imperfectly dissected. We aimed at deciphering the modifications occurring in vivo during the very early stages of AD, before the development of amyloid deposits, neurofibrillary tangles, neuronal death and inflammation.

The Chemokine MIP-1α/CCL3 impairs mouse hippocampal synaptic transmission, plasticity and memory.

Chemokines are signaling molecules playing an important role in immune regulations. They are also thought to regulate brain development, neurogenesis and neuroendocrine functions. While chemokine upsurge has been associated with conditions characterized with cognitive impairments, their ability to modulate synaptic plasticity remains ill-defined.

sAβPPα Improves Hippocampal NMDA-Dependent Functional Alterations Linked to Healthy Aging.

This study shows a decrease in soluble amyloid-β protein precursor-α (sAβPPα) levels, but no change in sAβPPβ, in the rat hippocampus during healthy aging, associated with the weaker expression of N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) in the CA1 area of hippocampal slices. Exogenous application of recombinant sAβPPα increases NMDAR activation in aged animals and could rescue the age-related LTP deficits described. In contrast, it does not affect basal synaptic transmission or glutamate release.

Cholesterol 24-hydroxylase defect is implicated in memory impairments associated with Alzheimer-like Tau pathology.

Alzheimer's disease (AD) is characterized by both amyloid and Tau pathologies. The amyloid component and altered cholesterol metabolism are closely linked, but the relationship between Tau pathology and cholesterol is currently unclear. Brain cholesterol is synthesized in situ and cannot cross the blood-brain barrier: to be exported from the central nervous system into the blood circuit, excess cholesterol must be converted to 24S-hydroxycholesterol by the cholesterol 24-hydroxylase encoded by the CYP46A1 gene.

Somatostatinergic systems: an update on brain functions in normal and pathological aging.

Somatostatin is highly expressed in mammalian brain and is involved in many brain functions such as motor activity, sleep, sensory, and cognitive processes. Five somatostatin receptors have been described: sst(1), sst(2) (A and B), sst(3), sst(4), and sst(5), all belonging to the G-protein-coupled receptor family. During the recent years, numerous studies contributed to clarify the role of somatostatin systems, especially long-range somatostatinergic interneurons, in several functions they have been previously involved in.

Omega-3 fatty acids deficiency aggravates glutamatergic synapse and astroglial aging in the rat hippocampal CA1.

Epidemiological data suggest that a poor ω3 status favoured by the low ω3/ω6 polyunsaturated fatty acids ratio in western diets contributes to cognitive decline in the elderly, but mechanistic evidence is lacking. We therefore explored the impact of ω3 deficiency on the evolution of glutamatergic transmission in the CA1 of the hippocampus during aging by comparing 4 groups of rats aged 6-22 months fed ω3-deficient or ω3/ω6-balanced diets from conception to sacrifice: Young ω3 Balanced (YB) or Deficient (YD), Old ω3 Balanced (OB) or Deficient (OD) rats. ω3 Deficiency induced a 65% decrease in the amount of docosahexaenoic acid (DHA, the main ω3 in cell membranes) in brain phospholipids, but had no impact on glutamatergic transmission and astroglial function in young rats.

Selective impairment of some forms of synaptic plasticity by oligomeric amyloid-β peptide in the mouse hippocampus: implication of extrasynaptic NMDA receptors.

Alzheimer's disease is characterized by the loss of memory and synaptic damage. Evidence is accumulating for a causal role of soluble oligomeric species of amyloid-β peptide (Aβo) in the impairment of synaptic plasticity and cognition but the precise mechanisms underlying these effects are still not clear. Synaptic plasticity such as long-term potentiation is thought to underlie learning and memory.

Reversal of age-related oxidative stress prevents hippocampal synaptic plasticity deficits by protecting D-serine-dependent NMDA receptor activation.

Oxidative stress (OS) resulting from an imbalance between antioxidant defenses and the intracellular accumulation of reactive oxygen species (ROS) contributes to age-related memory deficits. While impaired synaptic plasticity in neuronal networks is thought to underlie cognitive deficits during aging, whether this process is targeted by OS and what the mechanisms involved are still remain open questions. In this study, we investigated the age-related effects of the reducing agent N-acetyl-L-cysteine (L-NAC) on the activation of the N-methyl-D-aspartate receptor (NMDA-R) by its co-agonist D-serine, because alterations in this mechanism contribute greatly to synaptic plasticity deficits in aged animals.

A new neuronal target for β-amyloid peptide in the rat hippocampus.

In Alzheimer's disease, amyloid beta peptide (Aβ) accumulation is associated with hippocampal network dysfunction. Intrahippocampal injections of Aβ induce aberrant inhibitory septohippocampal (SH) network activity in vivo and impairment of memory processing. In the present study, we observed, after hippocampal Aβ treatment, a selective loss of neurons projecting to the medial septum (MS) and containing calbindin (CB) and/or somatostatin (SOM).

Continuous enriched environment improves learning and memory in adult NMRI mice through theta burst-related-LTP independent mechanisms but is not efficient in advanced aged animals.

Introduction: Effects of 3-month continuous environmental enrichment (EE) on cognitive abilities and on theta burst-related synaptic plasticity of CA1 hippocampal neuronal networks have been assessed in 6- and 20-month old NMRI female mice.

Results: EE decreased anxiety-like behavior and improved learning and memory performances in adult but not in aged mice. Electrophysiological results in CA1 hippocampal slices showed that basal synaptic transmission was not affected by EE in adult mice whereas it was partially improved in aged animals, even though not sufficient to rescue the decrease related to aging.

Decreased rhythmic GABAergic septal activity and memory-associated theta oscillations after hippocampal amyloid-beta pathology in the rat.

The memory deficits associated with Alzheimer's disease result to a great extent from hippocampal network dysfunction. The coordination of this network relies on theta (symbol) oscillations generated in the medial septum. Here, we investigated in rats the impact of hippocampal amyloid beta (Abeta) injections on the physiological and cognitive functions that depend on the septohippocampal system.

Protein phosphatase 1-dependent transcriptional programs for long-term memory and plasticity.

Gene transcription is essential for the establishment and the maintenance of long-term memory (LTM) and for long-lasting forms of synaptic plasticity. The molecular mechanisms that control gene transcription in neuronal cells are complex and recruit multiple signaling pathways in the cytoplasm and the nucleus. Protein kinases (PKs) and phosphatases (PPs) are important players in these mechanisms.

Reduction in glutamate uptake is associated with extrasynaptic NMDA and metabotropic glutamate receptor activation at the hippocampal CA1 synapse of aged rats.

This study aims to determine whether the regulation of extracellular glutamate is altered during aging and its possible consequences on synaptic transmission and plasticity. A decrease in the expression of the glial glutamate transporters GLAST and GLT-1 and reduced glutamate uptake occur in the aged (24-27 months) Sprague-Dawley rat hippocampus. Glutamatergic excitatory postsynaptic potentials recorded extracellularly in ex vivo hippocampal slices from adult (3-5 months) and aged rats are depressed by DL-TBOA, an inhibitor of glutamate transporter activity, in an N-Methyl-d-Aspartate (NMDA)-receptor-dependent manner.

Firing properties of anatomically identified neurons in the medial septum of anesthetized and unanesthetized restrained rats.

Cholinergic and GABAergic neurons in the medial septum-diagonal band of Broca (MS-DB) project to the hippocampus where they are involved in generating theta rhythmicity. So far, the functional properties of neurochemically identified MS-DB neurons are not fully characterized. In this study, MS-DB neurons recorded in urethane anesthetized rats and in unanesthetized restrained rats were labeled with neurobiotin and processed for immunohistochemistry against glutamic acid decarboxylase (GAD), parvalbumin (PV), and choline acetyltransferase (ChAT).

Partial inhibition of PP1 alters bidirectional synaptic plasticity in the hippocampus.

Synaptic plasticity is an important cellular mechanism that underlies memory formation. In brain areas involved in memory such as the hippocampus, long-term synaptic plasticity is bidirectional. Major forms of bidirectional plasticity encompass long-term potentiation (LTP), LTP reversal (depotentiation) and long-term depression (LTD).