Synaptic dysfunction plays a central role in Alzheimer's disease (AD), since it drives the cognitive decline. An association between a polymorphism of the adenosine A receptor (AR) encoding gene-ADORA2A, and hippocampal volume in AD patients was recently described. In this study, we explore the synaptic function of AR in age-related conditions. We report, for the first time, a significant overexpression of AR in hippocampal neurons of aged humans, which is aggravated in AD patients. A similar profile of AR overexpression in rats was sufficient to drive age-like memory impairments in young animals and to uncover a hippocampal LTD-to-LTP shift. This was accompanied by increased NMDA receptor gating, dependent on mGluR5 and linked to enhanced Ca influx. We confirmed the same plasticity shift in memory-impaired aged rats and APP/PS1 mice modeling AD, which was rescued upon AR blockade. This AR/mGluR5/NMDAR interaction might prove a suitable alternative for regulating aberrant mGluR5/NMDAR signaling in AD without disrupting their constitutive activity.
Reduction of A 2A receptor expression is one of the earliest events occurring in both Huntington's disease (HD) patients and mice overexpressing the N-terminal part of mutated huntingtin. Interestingly, increased activity of A 2A receptors has been found in striatal cells prone to degenerate in experimental models of this neurodegenerative disease. However, the role of A 2A receptors in the pathogenesis of HD remains obscure. In the present study, using A 2A Ϫ/Ϫ mice and pharmacological compounds in rat, we demonstrate that striatal neurodegeneration induced by the mitochondrial toxin 3-nitropropionic acid (3NP) is regulated by A 2A receptors. Our results show that the striatal outcome induced by 3NP depends on a balance between the deleterious activity of presynaptic A 2A receptors and the protective activity of postsynaptic A 2A receptors. Moreover, microdialysis data demonstrate that this balance is anatomically determined, because the A 2A presynaptic control on striatal glutamate release is absent within the posterior striatum. Therefore, because blockade of A 2A receptors has differential effects on striatal cell death in vivo depending on its ability to modulate presynaptic over postsynaptic receptor activity, therapeutic use of A 2A antagonists in Huntington's as well as in other neurodegenerative diseases could exhibit undesirable biphasic neuroprotective-neurotoxic effects.
Neural and mesenchymal stem cells have been proposed as alternative sources of cells for transplantation into the brain in neurodegenerative disorders. However, the endogenous factors controlling their engraftment within the injured parenchyma remain ill-defined. Here, we demonstrate significant engraftment of undifferentiated exogenous mesenchymal or neural stem cells throughout the lesioned area in a rat model for Huntington's disease, as late as 8 weeks post-transplantation. We show that stem cell factor (SCF), strongly up-regulated within host cells in the damaged striatum, is able to activate the SCF receptor c-kit and its signaling pathway and to promote the migration and proliferation of mesenchymal and neural stem cells in vitro. Furthermore, c-kit receptor blockade alters neural stem cell distribution within the lesioned striatum. Host SCF expression is observed in atypical cells expressing glial fibrillary acidic protein and doublecortin in the lesioned striatum and in migrating doublecortin-positive progenitors. Taken together, these data demonstrate that SCF produced in situ in the lesioned striatum is an important factor in promoting the engraftment of stem cells within the lesioned brain.
SV2C is an isoform of the synaptic vesicle 2 protein family that exhibits a particular pattern of brain expression with enriched expression in several basal ganglia nuclei. In the present study, we have investigated SV2C implication in both normal and pathological basal ganglia functioning with a peculiar attention to dopamine neuron containing regions. In SV2C-/- mice, the expression of tyrosine hydroxylase mRNA in midbrain dopaminergic neurons was largely and significantly increased and enkephalin mRNA expression was significantly decreased in the caudate-putamen and accumbens nucleus. The expression of SV2C was studied in two models of dopaminergic denervation (6-OHDA- and MPTP-induced lesions). In dopamine-depleted animals, SV2C mRNA expression was significant increased in the striatum. In order to further understand the role of SV2C, we performed behavioral experiments on SV2C-/- mice and on knock-down mice receiving an injection of adeno-associated virus expressing SV2C miRNA specifically in the ventral midbrain. These modifications of SV2C expression had little or no impact on behavior in open field and elevated plus maze. However, even if complete loss of SV2C had no impact on conditioned place preference induced by cocaine, the specific knock-down of SV2C expression in the dopaminergic neurons completely abolished the development of a CPP while the reaction to an acute drug injection remains similar in these mice compared to control mice. These results showed that SV2C, a poorly functionally characterized protein is strongly involved in normal operation of the basal ganglia network and could be also involved in system adaptation in basal ganglia pathological conditions.
These results show that remifentanil hydrochloride does not directly activate NMDA receptors. The NMDA current recorded after application of Ultiva is related to the presence of glycine. Induced NMDA current is potentiated by application of remifentanil hydrochloride through a pathway involving the mu-opioid receptor.
3-Nitropropionic acid (3NP) is a succinate dehydrogenase inhibitor classically used to create animal models of Huntington's disease (HD). However, the effects of this neurotoxin are highly variable in the Sprague-Dawley rat strain, impeding the interest of such model in neuroprotection assays. In the present study, we found that continuous s.c. infusion of 3NP in the Lewis rat strain produces homogeneous clinical impairments as well as highly reproducible striatal lesions according to their location and size. More especially, using quantitative reconstructions, we have determined, after 5 days of treatment, that the lesion was topologically reproducible in the lateral part of the striatum in all tested rats. Thus, 3NP-treated Lewis rat provides an improved animal model for testing neuroprotective strategies in HD.
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