Amyloid-β(25-35) Modulates the Expression of GirK and KCNQ Channel Genes in the Hippocampus

Abstract

During early stages of Alzheimer’s disease (AD), synaptic dysfunction induced by toxic amyloid-β (Aβ) is present before the accumulation of histopathological hallmarks of the disease. This scenario produces impaired functioning of neuronal networks, altered patterns of synchronous activity and severe functional deficits mainly due to hyperexcitability of hippocampal networks. The molecular mechanisms underlying these alterations remain unclear but functional evidence, shown by our laboratory and others, points to the involvement of receptors/channels which modulate neuronal excitability, playing a pivotal role in early Aβ-induced AD pathogenesis. In particular, two potassium channels that control neuronal excitability, G protein-coupled activated inwardly-rectifying potassium channel (GirK), and voltage-gated K channel (KCNQ), have been recently linked to Aβ pathophysiology in the hippocampus. Specifically, by using Aβ25-35, we previously found that GirK conductance is greatly decreased in the hippocampus, and similar effects have also been reported on KCNQ conductance. Thus, in the present study, our goal was to determine the effect of Aβ on the transcriptional expression pattern of 17 genes encoding neurotransmitter receptors and associated channels which maintain excitatory-inhibitory neurotransmission balance in hippocampal circuits, with special focus in potassium channels. For this purpose, we designed a systematic and reliable procedure to analyze mRNA expression by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) in hippocampal rat slices incubated with Aβ 25-35. We found that: 1) Aβ down-regulated mRNA expression of ionotropic GluN1 and metabotropic mGlu1 glutamate receptor subunits as previously reported in other AD models; 2) Aβ also reduced gene expression levels of GirK2, 3, and 4 subunits, and KCNQ2 and 3 subunits, but did not change expression levels of its associated GABAB and M1 receptors, respectively. Our results provide evidence that Aβ can modulate the expression of these channels which could affect the hippocampal activity balance underlying learning and memory processes impaired in AD.

Hippocampal long‐term synaptic depression and memory deficits induced in early amyloidopathy are prevented by enhancing G‐protein‐gated inwardly rectifying potassium channel activity

“…Given that Aβ has been shown to alter GirK channels at the molecular (May et al, ; Mayordomo‐Cava et al, ) and synaptic (Nava‐Mesa et al, ) levels, we asked whether blocking of GirK‐dependent signaling with TQ would interfere with synaptic plasticity depression induced by Aβ 1–42 . As lack of GirK channels has been shown to be deleterious for cognition (Slesinger et al, ) we first evaluated the effect of TQ (0.5 μM) on LTP induction.…”

“…Despite the apparent causal relationship of Aβ in the pathogenesis of AD, its mechanisms of action or main targets have not yet been established (Selkoe & Hardy, ). Previous experiments have showed that incubation of rat hippocampal slices with Aβ 25–35 produces a facilitation in LFS‐induced LTD (Cheng, Yin, Zhang, & Qi, ), causes a decrease in the expression of the Girk1‐4 subunits at the mRNA level (Mayordomo‐Cava et al, ) and, as TQ, a membrane depolarization and synaptic neurotransmission impairment by a reduction in GirK channels conductance (Nava‐Mesa et al, ). Aβ 25–35 , the active fragment of Aβ peptide, and Aβ 1–42 , a more relevant specie in AD patients, seem to share neurophysiopathological mechanisms as both induce an imbalance in the excitatory/inhibitory neurotransmission in the hippocampus that causes aberrant activity (Gutierrez‐Lerma, Ordaz, & Pena‐Ortega, ).…”

“…Hippocampal slices (3–4 per condition and per animal, n = 7) were incubated at room temperature in two different conditions, (a) ACSF or (b) ACSF enriched with Aβ 1–42 (0.5 μM), during different time periods (0, 30, 120 min). Time points for protein expression analysis where chosen based on our previous in vitro results (Mayordomo‐Cava et al, ). GIRK1 and 2 were evaluated as their heterotetramers are the prototypical Girk channels in the hippocampus (Fernandez‐Alacid, Watanabe, Molnar, Wickman, & Lujan, ).…”

“…It has been previously reported that Aβ induces a reduction in gene expression of hippocampal GirK subunits (Mayordomo‐Cava, Yajeya, Navarro‐Lopez, & Jimenez‐Diaz, ) and decreases GirK conductance inducing an increase in excitability in CA3 pyramidal neurons (Nava‐Mesa, Jimenez‐Diaz, Yajeya, & Navarro‐Lopez, ). We also found in behaving mice that GirK‐dependent signal enhancement rescued hippocampal functions in an in vivo mouse model of early Aβ pathology (Sanchez‐Rodriguez et al, , ).…”

G Protein-Gated K + Channel Ablation in Forebrain Pyramidal Neurons Selectively Impairs Fear Learning

“…Post-mortem forebrain samples from individuals with schizophrenia or bipolar disorder also show reduced GIRK mRNA levels (27). GIRK2 hypo-function is implicated in intellectual, cognitive and mental disabilities (28, 29), as well as elevated hippocampal network excitability in the early stages of AD (30). Mouse models of DS, including mice carrying an extra copy of the Girk2 gene (GIRK2 trisomy mice), exhibit enhanced GIRK channel activity in hippocampal pyramidal neurons, as well as disrupted hippocampal-dependent synaptic plasticity and deficits in contextual fear learning and memory (31, 32).…”