Dendritic vulnerability in neurodegenerative disease: Insights from analyses of cortical pyramidal neurons in transgenic mouse models

M949, Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA, 02118, USA.
Brain Structure and Function (Impact Factor: 4.57). 02/2010; 214(2-3):181-99. DOI: 10.1007/s00429-010-0244-2
Source: PubMed

ABSTRACT In neurodegenerative disorders, such as Alzheimer's disease, neuronal dendrites and dendritic spines undergo significant pathological changes. Because of the determinant role of these highly dynamic structures in signaling by individual neurons and ultimately in the functionality of neuronal networks that mediate cognitive functions, a detailed understanding of these changes is of paramount importance. Mutant murine models, such as the Tg2576 APP mutant mouse and the rTg4510 tau mutant mouse have been developed to provide insight into pathogenesis involving the abnormal production and aggregation of amyloid and tau proteins, because of the key role that these proteins play in neurodegenerative disease. This review showcases the multidimensional approach taken by our collaborative group to increase understanding of pathological mechanisms in neurodegenerative disease using these mouse models. This approach includes analyses of empirical 3D morphological and electrophysiological data acquired from frontal cortical pyramidal neurons using confocal laser scanning microscopy and whole-cell patch-clamp recording techniques, combined with computational modeling methodologies. These collaborative studies are designed to shed insight on the repercussions of dystrophic changes in neocortical neurons, define the cellular phenotype of differential neuronal vulnerability in relevant models of neurodegenerative disease, and provide a basis upon which to develop meaningful therapeutic strategies aimed at preventing, reversing, or compensating for neurodegenerative changes in dementia.

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Available from: Dara L Dickstein, Jan 20, 2014
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    • "Following the well-known relationship between form and function in biological systems, recent in vitro and in vivo studies have demonstrated that the morphology of spines relates closely to the function and plasticity of the synapses they belong to (Yuste et al., 2000; Trachtenberg et al., 2002; Mizrahi et al., 2004; Segal, 2005; Kasai et al., 2010). For example, the volume of the spine head is directly proportional to the area of the postsynaptic density and the number of synaptic vesicles docked at the presynaptic active zone (Harris and Stevens, 1989; Schikorski and Stevens, 1999), the number of postsynaptic receptors (Nusser et al., 1998), and hence to the size of synaptic currents and synaptic strength (Yuste and Bonhoeffer, 2001; Luebke et al., 2010). Two-photon uncaging of glutamate on large spines evoked "
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    ABSTRACT: Spines are small cytoplasmic extensions of dendrites that form the postsynaptic compartment of the majority of excitatory synapses in the mammalian brain. Alterations in the numerical density, size, and shape of dendritic spines have been correlated with neuronal dysfunction in several neurological and neurodevelopmental disorders associated with intellectual disability, including Rett syndrome (RTT). RTT is a progressive neurodevelopmental disorder associated with intellectual disability that is caused by loss of function mutations in the transcriptional regulator methyl CpG-binding protein 2 (MECP2). Here, we review the evidence demonstrating that principal neurons in RTT individuals and Mecp2-based experimental models exhibit alterations in the number and morphology of dendritic spines. We also discuss the exciting possibility that signaling pathways downstream of brain-derived neurotrophic factor (BDNF), which is transcriptionally regulated by MeCP2, offer promising therapeutic options for modulating dendritic spine development and plasticity in RTT and other MECP2-associated neurodevelopmental disorders.
    Frontiers in Neuroanatomy 09/2014; 8:97. DOI:10.3389/fnana.2014.00097 · 4.18 Impact Factor
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    • "Spines appear and disappear through life, but their turnover rate declines with the age and is regulated by the neuronal activity [18]. Dendritic spines undergo structural modifications when the synaptic strength is experimentally modified (e.g., by evoking long-term potentiation or long-term depression) [18] [22] [24]. "
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    BioMed Research International 06/2014; 2014:345305. DOI:10.1155/2014/345305 · 2.71 Impact Factor
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    • "At present there is considerable interest in examining the possible alterations to pyramidal cells associated with brain disease, and their role in memory, learning and cognition (Fiala et al., 2002; Benavides-Piccione et al., 2004; Spruston, 2008; Luebke et al., 2010; Penzes et al., 2011). Pyramidal cells are the most abundant neurons in the cortex (estimated to represent 70–80% of the total neuronal population), where they are the main source of excitatory (glutamatergic) synapses. "
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    ABSTRACT: The dendritic spines on pyramidal cells represent the main postsynaptic elements of cortical excitatory synapses and they are fundamental structures in memory, learning and cognition. In the present study, we used intracellular injections of Lucifer yellow in fixed tissue to analyse over 19 500 dendritic spines that were completely reconstructed in three dimensions along the length of the basal dendrites of pyramidal neurons in the parahippocampal cortex and CA1 of patients with Alzheimer's disease. Following intracellular injection, sections were immunostained for anti-Lucifer yellow and with tau monoclonal antibodies AT8 and PHF-1, which recognize tau phosphorylated at Ser202/Thr205 and at Ser396/404, respectively. We observed that the diffuse accumulation of phospho-tau in a putative pre-tangle state did not induce changes in the dendrites of pyramidal neurons, whereas the presence of tau aggregates forming intraneuronal neurofibrillary tangles was associated with progressive alteration of dendritic spines (loss of dendritic spines and changes in their morphology) and dendrite atrophy, depending on the degree of tangle development. Thus, the presence of phospho-tau in neurons does not necessarily mean that they suffer severe and irreversible effects as thought previously but rather, the characteristic cognitive impairment in Alzheimer's disease is likely to depend on the relative number of neurons that have well developed tangles.
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