. Aging and excitotoxic stress exacerbate neural circuit reorganization in amyloid precursor protein intracellular domain transgenic mice. Neurobiol Aging. 2011 Dec;32(12):2320.e1-9. PubMed.

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  1. This interesting report by Kaushik Ghosal and Sanjay Pimplikar describes seizure-related remodeling in the hippocampus of transgenic mice expressing AICD and the adapter protein Fe65 in excitatory neurons, extending a series of studies from this group on the effects of AICD overexpression in mice.

    At first glance, one is struck by the superficial similarity of the phenotype (seizures, mossy fiber sprouting, ectopic NPY, and calbindin depletion) to that of hAPP transgenic mice (Palop et al., 2003; Palop et al., 2007), which would raise the question of whether these changes in hAPP mice might be driven as much or more by AICD as by Aβ. On closer inspection, however, there are several important differences between the mouse models and the remodeling in AICD and hAPP transgenic mice, as the authors point out. First, the mossy fiber sprouting in AICD mice is in the inner molecular layer, onto the granule cell dendrites, and thus forms a recurrent feedback loop that would contribute to granule cell hyperexcitation. In hAPP mice, the aberrant mossy fiber sprouting is onto inhibitory basket cells (Palop et al., 2007), which would have the opposite effect on granule cell activity. Second, AICD mice do not have NPY-positive sprouting of inhibitory GABAergic interneurons onto granule cells dendrites in the molecular layer, as seen in hAPP mice. Thus, AICD mice lack two types of inhibitory sprouting found in hAPP mice and instead have a form of excitatory sprouting. These differences, combined with the fact that AICD levels are probably much lower in hAPP mice, which lack exogenous Fe65 needed to stabilize AICD and boost its levels, suggest that AICD is probably not driving the effects in hAPP mice, and that the remodeling in AICD mice is mechanistically distinct from that seen in hAPP mice.

    The current report, however, emphasizes the potential neurobiological effects of AICD. The AICD-induced sprouting pattern is similar to that classically described in temporal lobe epilepsy patients (Sutula et al., 1989). It will be interesting to follow this story as the mechanisms by which AICD induces epileptic activity and hippocampal remodeling are unraveled.

    References:

    . Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer's disease-related cognitive deficits. Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9572-7. Epub 2003 Jul 24 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.

    . Mossy fiber synaptic reorganization in the epileptic human temporal lobe. Ann Neurol. 1989 Sep;26(3):321-30. PubMed.