. Dendritic structural degeneration is functionally linked to cellular hyperexcitability in a mouse model of Alzheimer's disease. Neuron. 2014 Dec 3;84(5):1023-33. Epub 2014 Nov 13 PubMed.


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  1. The key finding in this paper is a reduction of the dendritic tree and some reduction of spines in about 1-year-old APP/PS1 mice. At least some studies suggest that this particular mouse is a good model of Alzheimer disease. Similar reduction in dendritic volume was found in patients with several neurodegenerative disorders, including Alzheimer disease.

    The next finding of the paper is predictable from neuronal cable theory, i.e., that smaller cellular volume (or dendritic volume) equates to higher neuronal excitability. The authors provide references in the introduction on these studies. The established theoretical framework, however, needed experimental confirmation and the present study shows convincingly that indeed the intrinsic excitability of neurons is increased in hippocampal CA1 pyramidal neurons from APP/PS1 mice.

    The next finding of the study, which was much less predicted from theory, is that anesthetized 1-year-old APP/PS1 mice display bursts of network activities. The nature of these bursts is unclear. There are at least two possibilities. One is that APP/PS1 mice have different sensitivity to anesthesia, and therefore these burst are appropriate to some anesthesia-related phenomena. The other possibility is more exciting. Are these bursts paroxysmal? Are they a signature of epileptic discharges? The shown spectrogram (Fig. 1 D) suggests that these bursts of network activity can be epileptiform.

    Indeed, several studies demonstrate that “young” Alzheimer patients (50 years old) have a high likelihood to develop epilepsy. Because 1-year-old mice more or less correspond to 40- to 50-year-old humans, they may reveal comorbidities related to the Alzheimer condition, namely epilepsy. To show this convincingly, we need in vivo behavioral and electrophysiological experiments on non-anesthetized mice that are 1 year and older.

  2. In this elegant study, Šišková et al. used a combination of approaches to examine the morphological and electrophysiological properties of pyramidal neurons in the CA1 region of the hippocampus in a transgenic mouse model of Alzheimer's disease amyloidosis. They provide a morphological explanation for abnormal hippocampal hyperexcitability in mice with high plaque load and memory impairment.

    By using in vivo whole-cell recordings, the team demonstrated that in 10- to 14-month-old APP/PS1 mice, CA1 neurons showed massively elevated firing rates and a frequent occurrence of action potential bursts when compared with age-matched wild-type mice. Recordings in slices confirmed and extended these in vivo results. Next, morphological analyses using confocal and super-resolution STED microscopy revealed that in the transgenic mice the dendrites of CA1 neurons had a reduced length and surface area as well as a reduced spine density. Subsequent modeling led the authors to conclude that this dendritic degeneration was sufficient to explain the hyperexcitability of CA1 neurons.

    The study nicely confirms previous work, which demonstrated Aβ related hyperactivity of neuronal circuits (see, e.g., Palop et al., 2007Busche et al., 2008Busche et al., 2012), but adds the important insight that such hyperexcitability—at least in an advanced disease stage—could be driven directly by neurodegeneration. I believe that the finding of this structure-function relation is very exciting and represents a major advance in our understanding of how Aβ pathology alters brain function at the level of individual neurons. This novel mechanism may also have broad implications for other diseases that are associated with neurodegeneration.

    The study raises a number of basic and disease-related questions. For instance, I noticed that in wild-type animals the CA1 neuronal firing frequency of ~3 Hz was much higher than that in previous studies reporting firing rates below 1 Hz under similar conditions (see, e.g., Misuzeki and Buzsaki, 2013; Grienberger et al., 2014). In addition, in the wild-type mice the team detected a surprisingly low number of action potential bursts in vivo (~7 percent) and after current injection in slices (~4 percent), while previous papers had reported a higher occurrence of bursting neurons (see, e.g., Graves et al., 2012). I wonder whether these differences are due to the older age of animals used by Šišková et al., which would be very interesting per se. Burst firing is widely regarded as a key property of hippocampal neurons and may serve important physiological functions, e.g., for synaptic plasticity (see, e.g., Lisman, 1997; Xu et al., 2012). Therefore, the paper should prompt further studies to more specifically evaluate the properties of bursting neurons in aging and in the disease state.

    It would be very interesting to see whether the observed effects are specific to Aβ-related structural deficits or can be found in other models of neurodegeneration as well. Furthermore, I wonder whether improving the morphological abnormalities—as has been reported by the use of locally applied antibodies against Aβ (see, e.g., Lombardo et al., 2003Brendza et al., 2005)—can rescue the functional deficits.


    . 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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    . Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2012 May 29;109(22):8740-5. Epub 2012 May 16 PubMed.

    . Preconfigured, skewed distribution of firing rates in the hippocampus and entorhinal cortex. Cell Rep. 2013 Sep 12;4(5):1010-21. Epub 2013 Aug 29 PubMed.

    . NMDA receptor-dependent multidendrite Ca(2+) spikes required for hippocampal burst firing in vivo. Neuron. 2014 Mar 19;81(6):1274-81. Epub 2014 Feb 20 PubMed.

    . Hippocampal pyramidal neurons comprise two distinct cell types that are countermodulated by metabotropic receptors. Neuron. 2012 Nov 21;76(4):776-89. PubMed.

    . Bursts as a unit of neural information: making unreliable synapses reliable. Trends Neurosci. 1997 Jan;20(1):38-43. PubMed.

    . Distinct neuronal coding schemes in memory revealed by selective erasure of fast synchronous synaptic transmission. Neuron. 2012 Mar 8;73(5):990-1001. PubMed.

    . Amyloid-beta antibody treatment leads to rapid normalization of plaque-induced neuritic alterations. J Neurosci. 2003 Nov 26;23(34):10879-83. PubMed.

    . Anti-Abeta antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic mice. J Clin Invest. 2005 Feb;115(2):428-33. PubMed.

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  1. Does Amyloid Shrink Neurons, Shorten Their Fuses?

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