P4‐001: Overactivation of NMDA receptors in the aged APPswe‐PS1dE9 brain, a mouse model of Alzheimer's disease

Le résumé fourni par la source

N-methyl-d-aspartate receptors (NMDA-R) are a subtype of glutamatergic ligand-gated ion channels with key roles in physiological brain function, most notably in learning and memory. Perturbations of NMDA-R mediated neuronal activity are thought to be involved in the pathophysiology of various brain disorders, including Alzheimer's disease (AD). We have examined the regional activation state of NMDA-R in a mouse model of AD, using in vitro and ex vivo autoradiography of [3 H]MK-801 binding sites. For in vitro studies, coronal brain sections of drug naive, male APPswe-PS1dE9 and control mice were either prewashed and incubated for 4 hr with 20 nM [3 H]MK-801 in the presence of 10 μM glutamate and 30 μM glycine (conventional protocol), or were directly labeled with [3 H]MK-801 (in situ binding protocol). Non-specific binding was determined in adjacent brain sections in the presence of GMOM, an experimental NMDA-R antagonist. For ex vivo autoradiography, non-anaesthetized transgenic and control mice were injected with either saline (10 ml/kg, i.p) or ketamine (50 mg/kg, i.p), followed 15 min later by a tail vein injection of [3 H]MK-801 (200 μ Ci/kg). Total and non-specific binding was determined in brains of saline and ketamine-treated mice, respectively. The distribution pattern of [3 H]MK-801 binding sites was similar between control and transgenic animals. There was a significant, age-dependent genotype effect on specific NMDA-R binding, both in situ and ex vivo. [3 H]MK-801 binding levels were region-specifically increased in the hippocampus of 13 month-old APPswe-PS1dE9 mice compared to age-matched controls. NMDA-R may become over-active in the APPswe-PS1dE9 brain, in an age-dependent manner. Our findings hold relevance both for identifying new functional targets for molecular imaging in AD, and for the development of novel drugs targeting NMDA-R.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.