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Review
. 2015 Aug 25:9:318.
doi: 10.3389/fncel.2015.00318. eCollection 2015.

Gene expression parallels synaptic excitability and plasticity changes in Alzheimer's disease

Carlos A Saura  1 , Arnaldo Parra-Damas  1 , Lilian Enriquez-Barreto  1
Affiliations
Review

Gene expression parallels synaptic excitability and plasticity changes in Alzheimer's disease

Carlos A Saura et al. Front Cell Neurosci. .

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by abnormal accumulation of β-amyloid and tau and synapse dysfunction in memory-related neural circuits. Pathological and functional changes in the medial temporal lobe, a region essential for explicit memory encoding, contribute to cognitive decline in AD. Surprisingly, functional imaging studies show increased activity of the hippocampus and associated cortical regions during memory tasks in presymptomatic and early AD stages, whereas brain activity declines as the disease progresses. These findings suggest an emerging scenario where early pathogenic events might increase neuronal excitability leading to enhanced brain activity before clinical manifestations of the disease, a stage that is followed by decreased brain activity as neurodegeneration progresses. The mechanisms linking pathology with synaptic excitability and plasticity changes leading to memory loss in AD remain largely unclear. Recent studies suggest that increased brain activity parallels enhanced expression of genes involved in synaptic transmission and plasticity in preclinical stages, whereas expression of synaptic and activity-dependent genes are reduced by the onset of pathological and cognitive symptoms. Here, we review recent evidences indicating a relationship between transcriptional deregulation of synaptic genes and neuronal activity and memory loss in AD and mouse models. These findings provide the basis for potential clinical applications of memory-related transcriptional programs and their regulatory mechanisms as novel biomarkers and therapeutic targets to restore brain function in AD and other cognitive disorders.

Keywords: Alzheimer’s disease; Aβ; gene expression; memory; neurodegeneration; transcriptome.

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Figures

FIGURE 1
FIGURE 1
Hippocampal circuitry in the mouse brain. Modified original drawing of Santiago Ramón y Cajal’s (1911, left) and schematic diagram (right) of the rodent hippocampal circuitry. The picture shows the flux of excitatory projections (arrows) from entorhinal cortex (EC) neurons (green) directly to CA1 (orange) or CA3 (red) hippocampal pyramidal neurons or indirectly through projections to the dentate gyrus (DG, blue) through the perforant pathway. DG granule neurons project along the mossy fibers to CA3 pyramidal neurons. CA3 axons project through the Schaffer collaterals to CA1 pyramidal neurons, which finally project to the subiculum and deep EC IV- VI layers.
FIGURE 2
FIGURE 2
Age-dependent pathological, synaptic plasticity and associative memory changes in APP transgenic mice. (A) Brain sections of 3–6 months-old APPSw,Ind (J20) transgenic mice (APP) stained with an anti-Aβ antibody revealing the presence of amyloid plaques in the hippocampus at 6 months. (B) Contextual associative memory in one-shock contextual fear conditioning task. Three and six month-old APP mice exhibit significantly reduced levels of freezing at 24 h indicating disruption of long-term associative memory. Data represent the mean ± SEM. ∗P < 0.05, ∗∗P < 0.0001. (C), Time course of LTP induction at the CA1 Schaffer collaterals after theta burst stimulation (TBS) in 3- and 6-months old non-transgenic (control) and APP mice (n = 5–7). Notice the differential LTP in APP mice at 3 months (up) and 6 months (down) compared to the respective non-transgenic (control) mice. fEPSP, field excitatory postsynaptic potentials. Images are adapted from Saura et al. (2005).
FIGURE 3
FIGURE 3
Hypothetical model linking expression of synaptic genes and neuronal and memory network activities during AD progression. In healthy state, gene transcription controls expression of synaptic genes to maintain neuronal activity and synaptic plasticity in active memory circuits. In prodromal and very early AD stages, pathological changes increase expression of synaptic genes contributing to inhibitory/excitatory imbalance resulting in enhancement of synaptic excitability and plasticity in memory circuits. At intermediate and severe AD stages, sustained neuronal dysfunction causes transcriptional deregulation of synaptic genes resulting in synapse dysfunction and plasticity impairments, which contributes to memory network disruption and neurodegeneration.
FIGURE 4
FIGURE 4
Temporal progression of pathological and transcriptional changes in aging and AD. The diagram represents the hypothetical temporal progression of memory deficits, expression of synaptic genes, medial temporal lobe (MTL) activity and Aβ pathology during aging and AD. Enhanced brain activity at prodromal AD stages is associated with increased expression of synaptic genes, whereas decreased brain activity parallels reduction of synaptic genes as the disease progresses.
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