Dendritic spine dysgenesis in Rett syndrome - PubMed (original) (raw)

Dendritic spine dysgenesis in Rett syndrome, and intracellular signaling cascades involved in spine plasticity mediated by BDNF and IGF-1. (A) Confocal images of human CA1 pyramidal neurons in hippocampal sections from autopsy material labeled with DiI. Neurons from RTT individuals have lower dendritic spine density than those from typically developing individuals (Non-ID, non-intellectually disabled). **P < 0.01 (adapted from Chapleau et al., 2009a). (B) Confocal images of apical dendritic segments (top) of eYFP-expressing CA1 pyramidal neurons in 11 days in vitro hippocampal slice cultures prepared from postnatal day-5 wildtype (WT) and _Mecp_2 knockout (KO) mice, and their corresponding surface-rendered reconstructions (bottom). (C) Schematic diagram of an exemplary excitatory synapse on a dendritic spine of a pyramidal neuron in the hippocampus. We highlight the intracellular signaling cascades that mediate the effects of BDNF and IGF-1 on structural plasticity of spines. TrkB receptors are activated upon binding of BDNF, leading to dimerization and auto-phosphorylation. This process allows for the binding of adaptor proteins to their intracellular domain, and the subsequent activation of Ras/ERK, PI3K, and PLCγ (reviewed by Huang and Reichardt, 2003). All these pathways have been implicated in the effects of BDNF on dendritic spines (highlighted in red, see text for references). Potential therapies for the treatment of RTT act on these pathways (highlighted in green, see text for details and references): LM22A-4 binds and activates TrkB receptors directly (Massa et al., 2010); activation of IGF-1 receptors triggers the PI3K and Ras/ERK signaling pathways (Zheng and Quirion, 2004). DCV, dense core vesicle; Glu, glutamate; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; NMDAR, _N_-methyl-

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-aspartate receptor; mGluR, metabotropic glutamate receptor; ER, endoplasmic reticulum; RyR, ryanodine receptor; PIP2, phosphatidylinositol 4,5 bisphosphate; DAG, diacylglycerol; IP3, inositol triphosphate; IP3R, IP3 receptor; PKC, protein kinase C; SH-2, src homology domain 2; SHC, SH-2-containing protein; Grb2, growth factor receptor-binding protein 2; GAB1, Grb2-associated-binding protein 1; SOS, nucleotide exchange factor son-of-sevenless; Frs2, fibroblast growth factor receptor substrate 2; AKT, protein kinase B; Ras, rat sarcoma proto-oncogenic G-protein; Raf, proto-oncogenic serine/threonine protein kinase; MAPK, mitogen-activated protein kinase; MEK, MAPK kinase; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element-binding protein; IGF-1R, IGF-1 receptor; IRS-1, insulin receptor substrate 1.