"This is an important paper because it identifies one molecular explanation for the brake failure,” noted Jeffrey Noebels, Baylor College of Medicine, Houston, Texas, in an e-mail to Alzforum. Nav1.1 is encoded by the SCN1A gene, and mutations in it are responsible for epilepsies of varying severity (see Catterall et al., 2010). "Here the authors show that, through unknown mechanisms, excess Aβ peptide can result in a similar loss of sodium channel function in the same type of interneuron," wrote Noebels.

In 2007, Palop, with Lennart Mucke, also at Gladstone, and colleagues showed silent seizures in human amyloid precursor protein (APP)-expressing J20 mice. These animals lay down amyloid plaques accompanied by gliosis, exhibit signs of synaptic alteration, perform poorly in learning and memory tasks, and behave abnormally. The mice do not convulse overtly, but they freeze in their cages, and electroencephalography (EEG) recordings detected wild fluctuations in neural activity during those times (see ARF related news story on Palop et al., 2007). In the current paper, the research group asked when the aberrant neural activity happens and what causes it.

First author Laure Verret looked for clues in spikes of neural activity detectable by EEG. These are small epileptic discharges that are less intense than seizures but more frequent and easily quantified. In hAPPJ20 mice, spikes clustered during troughs in γ activity, that is, coordinated oscillations between 20 and 80 Hz. In contrast, during periods of intense γ waves, spiking stopped. Since γ activity is generated by parvalbumin (PV)-expressing inhibitory neurons, the researchers examined these cells more closely. Patch-clamp recordings showed that PV interneurons from J20 mice were more depolarized and produced action potentials of lower amplitude than those from control mice.

Since action potentials depend on voltage-gated sodium channels, the researchers looked to the core alpha subunits of four main sodium channels expressed in the central nervous system. They found that in the parietal cortex, the hAPP-expressing mice made less Nav1.1 mRNA and protein. Nav1.1 was similarly reduced in postmortem parietal cortices of 22 people who had suffered from AD, though it is unknown if any of them had seizure-like activity. The authors further found that the voltage-gated sodium channel blockers riluzole and phenytoin suppressed γ oscillations, led to more epileptiform activity, and worsened context-dependent memory in J20 mice. These blockers also bring on more seizures in human epilepsies resulting from loss-of-function mutations in Nav1.1 (see Liao et al., 2010). Riluzole is an ALS drug and phenytoin an anticonvulsant—their actions depend on blocking sodium channels in different cellular contexts. On the other hand, crossing hAPP mice to Nav1.1-overexpressing mice rescued γ activity, spiking abnormalities and cognition, and made the double-crosses long-lived.

"This paper identifies one of the possible mechanisms of this overexcitation—the reduction of neuron activity in inhibitory cells," Palop said. But the Nav1.1 channel subunit could be but one potential reason for network abnormalities, he said. "I'm sure more mechanisms will be discovered."

The larger point is that PV cells and γ activity may be therapeutic targets for AD, Palop told Alzforum. Behavioral interventions or drugs that enhance γ activity or reduce network hyperactivity could benefit cognitive function in the face of elevated Aβ, while γ-reducing drugs could actually worsen cognitive function in patients with AD.

Heikki Tanila, University of Eastern Finland, Kuopio, considered the evidence of sodium channel deficits in this model convincing. Tanila was not involved in this work. Researchers need to see if sodium channel deficits turn up in other transgenic animals, as well, he said. "Talking with colleagues, it looks like most of the APP transgenic mouse lines have epilepsy," he said, although he knows of only two that have been extensively characterized. Aside from Palop's hAPPJ20 model, Tanila's group has examined APPswe/PS1dE9 mice. These do have seizures, but unlike the hAPPJ20 line, they show increased γ activity, rather than reduced, and phenytoin treatment suppressed spikes instead of promoting them (see ARF related news story on Minkeviciene et al., 2009). "It's likely that we have more than one mechanism behind seizures in APP transgenic mice," Tanila said. He is also curious to know if reduced Nav1.1 levels are present in hAPPJ20 mice before amyloid-β starts to accumulate in the brain.

The findings not only propose future targets for AD therapeutics, but further tie AD to epilepsy, said Helen Scharfman, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, who was not part of this study. "The data would suggest there is a lot more than plaques and tangles" to AD, she added. She suggested that comparing the onset of seizure activity with that of plaque accumulation could help scientists figure out how abnormal activity and plaques affect one another. Additionally, the effects of sodium channel restoration on Aβ accumulation should be examined next, she said.

It is unclear why Nav1.1 would fall in transgenic mouse models or human patients in the first place. Here, previous work by Dora Kovacs, Massachusetts General Hospital, Boston, could be relevant. Kovacs showed that overexpression of the APP-cleaving enzyme BACE1 leads to abnormal Nav1.1 processing and compromises the channel’s insertion into neuronal membranes of adult hippocampal neurons. A lack of these channels could dampen excitability and enhance seizure activity (see ARF related news story).—Gwyneth Dickey Zakaib.

Reference:
Verret L, Mann EO, Hang GB, Barth AMI, Cobos I, Ho K, Devidze N, Masliah E, Kreitzer AC, Mody I, Mucke L, Palop JJ. Inhibitory Interneuron Deficit Links Altered Network Activity and Cognitive Dysfunction in Alzheimer Model. Cell 2012 April 27;(149):708-721. Abstract