Age-Dependent Impairment of Spine Morphology and Synaptic Plasticity in Hippocampal CA1 Neurons of a Presenilin 1 Transgenic Mouse Model of Alzheimer's Disease

Abstract

Presenilin 1 (PS1) mutations are responsible for a majority of early onset familial Alzheimer's disease (FAD) cases, in part by increasing the production of A␤ peptides. However, emerging evidence suggests other possible effects of PS1 on synaptic dysfunction where PS1 might contribute to the pathology independent of A␤. We chose to study the L286V mutation, an aggressive FAD mutation which has never been analyzed at the electrophysiological and morphological levels. In addition, we analyzed for the first time the long term effects of wild-type human PS1 overexpression. We investigated the consequences of the overexpression of either wild-type human PS1 (hPS1) or the L286V mutated PS1 variant (mutPS1) on synaptic functions by analyzing synaptic plasticity and associated spine density changes from 3 to 15 months of age. We found that mutPS1 induces a transient increase observed only in 4-to 5-month-old mutPS1 animals in NMDA receptor (NMDA-R)-mediated responses and LTP compared with hPS1 mice and nontransgenic littermates. The increase in synaptic functions is concomitant with an increase in spine density. With increasing age, however, we found that the overexpression of human wild-type PS1 progressively decreased NMDA-R-mediated synaptic transmission and LTP, without neurodegeneration. These results identify for the first time a transient increase in synaptic function associated with L286V mutated PS1 variant in an age-dependent manner. In addition, they support the view that the PS1 overexpression promotes synaptic dysfunction in an A␤-independent manner and underline the crucial role of PS1 during both normal and pathological aging.

Influence of aging and neurodegeneration on dendritic spine morphology

“…There is some evidence demonstrating spine morphological plasticity with learning [20][21][22][23][24][25], as well as evidence that the converse hypothesis may be true; that is, failure of spine formation and morphological plasticity may contribute to impairments in cognition [26]. Additional support for the latter hypothesis comes from studies that report alterations of spine numbers and morphology in animal models of aging [27][28][29][30][31][32] or neurodegenerative disease [33][34][35][36][37][38][39], both of which are characterized by compromised cognitive function.…”

Excitability governs neural development in a hippocampal region specific manner

“…Spines were classified as mushroom, stubby, thin or other by a blinded experimenter. Spines were defined as follows: mushroom, where the head width was >0.5 μm and at least twice the neck width; stubby, where there was no neck and the spine length and head width were approximately the same; thin, where the head width was <0.5 μm, with the spine length greater than the width; and other was any spine that did not clearly fit any of these categories owing to its odd shape (Sorra and Harris, 2000;Vanderklish and Edelman, 2002;Auffret et al, 2009;Dumitriu et al, 2010).…”

D-Serine in Neuropsychiatric Disorders: New Advances

“…Individuals with AD or MCI have fewer NMDARs in the frontal cortex and hippocampus [156,157]. In the genetic mouse model of AD, expression of surface NMDARs in neurons is decreased [158] and NMDAR-mediated response is impaired progressively with age [159,160]. In addition to reduced number of NMDARs, disrupted glutamatergic neurotransmission [146], decreased CSF concentrations of excitatory amino acids [161], decreased serum levels of DSR [162], and reduced D-aspartate uptake [163] are also noted in AD.…”