. Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell. 2012 Apr 27;149(3):708-21. PubMed.


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  1. The incidence of epilepsy is dramatically elevated in humans with early onset Alzheimer’s disease, in particular, those bearing mutations in FAD genes (APP, PS1, PS2, trisomy 21) as well as almost every genetically engineered mouse model that overexpresses Aβ peptide in the brain. However, clinicians who work closely with dementia patients are reluctant to consider the two disorders as related, since behavioral convulsions are brief and infrequent, and the steady cognitive decline of AD is unrelenting and accompanied by brain atrophy and cell death.

    However, the presence of electrical rhythm disturbances, particularly when they occur in memory-related hippocampal networks, are not obvious; a patient may display only momentary confusion and amnesia. These seizures are also a cause of cell death and atrophy. And any neurological disorder that features neuronal degeneration is susceptible to brain rhythm disturbances at some stage, particularly once inhibitory synapses lose their ability to brake neuronal firing patterns. During this period when the brakes are failing, traffic is destabilized, and a true epileptic seizure may occur. Thus, the seizure itself is simply a warning light, telling us that underlying brain rhythms and information flow are abnormal.

    This is an important paper because it identifies one molecular explanation for the brake failure, namely, a loss of Scn1a sodium channel function in inhibitory interneurons. These channels provide the firing power for interneurons to suppress excess excitability. This defect has been previously discovered in children who inherit a defective Scn1a gene and display a spectrum of epilepsy from mild to severe. Here, the authors show that, through unknown mechanisms, excess Aβ peptide can also result in a similar loss of sodium channel function in these same interneurons, thus strengthening the functional link between the two disorders. Restoring the sodium channels to their normal levels by genetically inserting extra copies of the gene allowed recovery of more normal brain rhythms.

    There is still great uncertainty, however, as to how closely mouse models of Aβ overexpression mimic the human disorder. Many of these models lack features that may be critical to both the mechanism and therefore the correct treatment to reverse human dementia. For example, neuronal cell loss is minimal in many mouse models, allowing for more dramatic recovery with experimental therapies. And the right antiepileptic drug for Aβ toxicity has not yet been discovered.

    However, if recognized and treated correctly, reversing brain rhythm disturbances and epilepsy early in the course of cognitive decline may prove to be a powerful way to preserve memory in Alzheimer’s disease patients. I won’t be surprised if this finding stimulates research in Alzheimer’s disease to move even more aggressively to identify a drug that will strengthen the function of inhibitory interneurons.

  2. I think this work is really interesting and reinforces the hypothesis that synchrony mediated by inhibition is crucial for brain computation, and these synchrony mechanisms are altered in familial or sporadic forms of AD.

  3. In my opinion, one of the important contributions of this study is that it proposes a novel molecular mechanism underlying AD pathogenesis in addition to Aβ synaptotoxicity on excitatory neurons. Dr. Palop’s team nicely showed that parvalbumin-positive GABAergic neurons (PV neurons) were not fully functional in hAPPJ20 AD mice. They found mRNA and protein levels of Nav1.1 voltage-gated sodium channels were significantly decreased in these neurons, especially in the parietal cortical region. Importantly, restoration of Nav1.1 levels not only rescued the inhibitory neuronal deficits, but also reduced memory deficits and premature mortality in these mice without significantly affecting Aβ peptide levels. Aβ accumulation may directly or indirectly regulate Nav1.1 transcription in PV neurons.

    Previously, we found that Nav1.1 mRNA and protein levels were also regulated by the intracellular domain of the neuronal voltage-gated sodium channel β2 subunit (Navβ2), generated by BACE1 and presenilin/γ-secretase cleavages of Navβ2 (Kim et al., 2007; Kovacs et al., 2010; Kim et al., 2011). The human APPswe/Ind transgene overproduced in hAPPJ20 mice, and endogenous Navβ2 may compete for the BACE1/γ-secretase-mediated cleavages in certain subsets of neurons, potentially contributing to the Nav1.1 decrease in these mice. Therefore, it will be interesting to explore Navβ subunit processing in PV neurons in this system. Of course, many issues need to be addressed before any of this might result in a clinical trial, including the availability of specific pharmacological modulators of Nav1.1 and/or PV neurons, additional proof-of-concept experiments with different AD models, the potential contribution of other voltage-gated ion channels to the PV neuron deficits such as Nav1.6 shown in this study, and further exploration of the underlying molecular mechanisms. However, this exciting study suggests that enhancing Nav1.1 activity/PV neuron function may reduce Alzheimer’s disease-related neuronal deficits in AD patients.


    . BACE1 regulates voltage-gated sodium channels and neuronal activity. Nat Cell Biol. 2007 Jul;9(7):755-64. PubMed.

    . Reduced sodium channel Na(v)1.1 levels in BACE1-null mice. J Biol Chem. 2011 Mar 11;286(10):8106-16. PubMed.

    . Alzheimer's secretases regulate voltage-gated sodium channels. Neurosci Lett. 2010 Dec 10;486(2):68-72. PubMed.

    . Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron. 2007 Sep 6;55(5):697-711. PubMed.

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