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Section MOLECULAR NEUROSCIENCE
We and others have previously demonstrated that patients with BBS have significantly decreased hippocampal and neocortical volumes. The exact mechanisms of hippocampal dysgenesis and reduced cortex volume in BBS are not known, however, one of the plausible explanations could be a reduced neuroplasticity.
It is widely believed that adult neurogenesis as well as regulation of dendritic spine formation is an important component of neuronal plasticity. We speculated that cognitive impairment in BBS might result from impaired neuroplasticity. Using BBS knockout mice models we have shown a significant reduction in adult neurogenesis of Bbs4 and Bbs5 mice. Moreover, we have shown global reduction of dendritic spines (including the hippocampus) and discovered that the spine loss occurs within the first 3 postnatal weeks resulting from increased autophagy during this period. Most strikingly we have confirmed that the plasticity of spines can be repaired by the introduction of aerobic exercise in these mice.
Neuronal Store Operated Calcium Entry as Novel Therapetic Target for Treatment of Alzheimer's Disease
Ilya Bezprozvanny
1,2 *
1 Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;
2 Laboratory of Molecular Neurodegeneration, St Petersburg State Polytechnical University, St Petersburg, 195251, Russia. * Presenting e-mail: mnlabspb@gmail.com
Memory loss in Alzheimer's disease (AD) results from "synaptic failure". Mushroom dendritic spine structures are essential for memory storage and the loss of mushroom spines may explain memory defects in aging and AD. To understand the basis for memory loss in AD we performed a series of mechanistic studies of hippocampal synap-tic spines in mouse models of familial AD (FAD). In our experiments we used presenilin 1 (PS1) M146V knockin (PS1KI) and APPKI models of FAD. In the course of these studies we discovered an existence of spine maintenance pathway that is mediated by neuronal store-operated Ca2+ entry (nSOC) in postsynaptic spines (Sun et al, 2014). We established that nSOC pathway plays a key role in stability of mushroom spines by constitutively activating synap-tic CaMKII kinase. We further demonstrated that synaptic nSOC is controlled by stromal interaction molecule 2 (STIM2) and that STIM2-nSOC-CaMKII pathway is compromised in PS1KI and APPKI neurons, in aging neurons and in sporadic AD brains due to downregulation of STIM2 protein (Sun et al., 2014; Zhang at al 2015). Moreover, we have demonstrated that expression of STIM2 protein rescues synaptic nSOC and mushroom spine loss in PS1KI and APPKI hippocampal neurons (Sun et al., 2014; Zhang at al 2015) and protects mushroom spines from amyloid synaptotoxicity (Popugaeva at al, 2015). These studies suggested that STIM2-nSOC pathway is a potentially important AD therapeutic target, and that activators and positive modulators of this pathway may have a utility for treatment of synaptic loss and memory decline in aging and AD.
References
1. Suya Sun, Hua Zhang, Jie Liu, Elena Popugaeva, Nan-Jie Xu, Stefan Feske, Charles L. White, III, and Ilya Bezprozvanny (2014) Reduced Synaptic STIM2 Expression and Impaired Store-Operated Calcium Entry Cause Destabilization of Mature Spines in Mutant Presenilin Mice. Neuron, vol 82, pp 79-93.
2. Elena Popugaeva, Ekaterina Pchitskaya, Anastasiya Speshilova, Sergey Alexandrov, Hua Zhang, Olga Vlasova, Ilya Bezprozvanny (2015) STIM2 protects hippocampal mushroom spines from amyloid synaptotoxicity. Molecular Neurodegeneration, 10:37.
3. Hua Zhang, Lili Wu, Ekaterina Pchitskaya, Olga Zakharova, Takashi Saito, Takaomi Saido and Ilya Bezprozvanny (2015) Neuronal store-operated calcium entry and mushroom spine loss in amyloid precursor protein knock-in mouse model of Alzheimer's disease. J. Neuroscience, vol 35, pp 13275-13286.
The 2.2-Angstrom Resolution Crystal Structure of the Carboxy-terminal Region of Ataxin-3
Ilya Bezprozvanny
1,2
1 Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;
2 Laboratory of Molecular Neurodegeneration, St Petersburg State Polytechnical University, St Petersburg, 195251, Russia. * Presenting e-mail: mnlabspb@gmail.com
Section MOLECULAR NEUROSCIENCE
Memory loss in Alzheimer's disease (AD) results from "synaptic failure". Mushroom dendritic spine structures are essential for memory storage and the loss of mushroom spines may explain memory defects in aging and AD. To understand the basis for memory loss in AD we performed a series of mechanistic studies of hippocampal synaptic spines in mouse models of familial AD (FAD). In our experiments we used presenilin 1 (PS1) M146V knockin (PS1KI) and APPKI models of FAD.
In the course of these studies we discovered an existence of spine maintenance pathway that is mediated by neuronal store-operated Ca2+ entry (nSOC) in postsynaptic spines (Sun et al, 2014). We established that nSOC pathway plays a key role in stability of mushroom spines by constitutively activating synaptic CaMKII kinase. We further demonstrated that synaptic nSOC is controlled by stromal interaction molecule 2 (STIM2) and that STIM2-nSOC-CaMKII pathway is compromised in PS1KI and APPKI neurons, in aging neurons and in sporadic AD brains due to downregulation of STIM2 protein (Sun et al., 2014; Zhang at al 2015). Moreover, we have demonstrated that expression of STIM2 protein rescues synaptic nSOC and mushroom spine loss in PS1KI and APPKI hippocampal neurons (Sun et al., 2014; Zhang at al 2015) and protects mushroom spines from amyloid synaptotoxicity (Popugaeva at al, 2015). These studies suggested that STIM2-nSOC pathway is a potentially important AD therapeutic target, and that activators and positive modulators of this pathway may have a utility for treatment of synaptic loss and memory decline in aging and AD.
References
1. Suya Sun, Hua Zhang, Jie Liu, Elena Popugaeva, Nan-Jie Xu, Stefan Feske, Charles L. White, III, and Ilya Bezproz-vanny (2014) Reduced Synaptic STIM2 Expression and Impaired Store-Operated Calcium Entry Cause Destabilization of Mature Spines in Mutant Presenilin Mice. Neuron, vol 82, pp 79-93.
2. Elena Popugaeva, Ekaterina Pchitskaya, Anastasiya Speshilova, Sergey Alexandrov, Hua Zhang, Olga Vlasova, Ilya Bezprozvanny (2015) STIM2 protects hippocampal mushroom spines from amyloid synaptotoxicity. Molecular Neurodegeneration, 10:37.
3. Hua Zhang, Lili Wu, Ekaterina Pchitskaya, Olga Zakharova, Takashi Saito, Takaomi Saido and Ilya Bezprozvanny (2015) Neuronal store-operated calcium entry and mushroom spine loss in amyloid precursor protein knock-in mouse model of Alzheimer's disease. J. Neuroscience, vol 35, pp 13275-13286.
Shaping the Dendritic Tree: the Role of Arhgap33 in Neocortical Development and Disease
Steffen Schuster1, Marion Rivalan2, Ulf Strauss3, Victor Tarabykin4, Marta Rosârio1*
1 Dendritic Development, Institute of Cell and Neurobiology, Charité Universitätsmedizin, Berlin, Germany;
2 Humboldt University Berlin, Institute of Cognitive Neurobiology, Charité Universitätsmedizin Berlin;
3 Ionic Current Development, Institute of Cell and Neurobiology, Charité Universitätsmedizin Berlin;
4 Cortical Development, Institute of Cell and Neurobiology, Charité Universitätsmedizin,Berlin. * Presenting e-mail: marta.rosario@charite.de
Neuropsychiatrie developmental disorders, such as autism spectrum disorders (ASD) and schizophrenia, are typically characterized by alterations in social behavior. At a cellular level, these conditions have been linked to aberrant development and maturation of the dendritic tree. We show here that the Cdc42 GTPase-activating multiadaptor protein, NOMA-GAP/ARHGAP33 regulates autism-like social behavior in the mouse as well as the formation of the dendritic tree and its maturation into a synaptically-connected branched structure (1, 2). ARHGAP33-deficient mice show cortical thinning associated with poorly branched dendritic trees. We demonstrate that inhibition of the small GTP-binding protein Cdc42 in postmitotic neurons is necessary for activation of the actin-binding protein cofilin and hence for proper branching of the neuronal dendritic tree during development of the mammalian neocortex. Furthermore, we demonstrate that these early steps are dependent on ARHGAP33, which acts as the main GTPase-activating protein for Cdc42 during neocortical development.
ARHGAP33 also has critical functions in the maturation of dendritic spines and in synapse formation in the neocortex. Surprisingly, we show that these later developmental functions are independent of its Cdc42 GAP activity.
However we show that ARHGAP33 also directly interacts with several members of the MAGUK family of scaffold proteins and that, in mature neurons, it concentrates at the postsynaptic site. Furthermore we show that ARHGAP33 regulates the phosphorylation and subcellular localization of the MAGUK family protein and major postsynaptic component, PSD-95 as well as surface expression of the AMPA receptor, thereby providing a molecular basis for autism-like social behavior in the absence of ARHGAP33.
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