The development of dendritic spines is thought to be crucial for synaptic plasticity.Dendritic spines are retracted upon EphA4 activation, but the mechanisms that control this process are not well understood. Here we report an important role of Cdk5 in EphA4-dependent spine retraction. We find that blockade of Cdk5 activity inhibits ephrin-A1-triggered spine retraction and reduction of mEPSC frequency at hippocampal synapses.Activation of EphA4 results in the recruitment of Cdk5 to EphA4, leading to the tyrosine phosphorylation and activation of Cdk5. EphA4 and Cdk5 then enhance the activation of ephexin1, a GEF that regulates RhoA activation. We show that the association between EphA4 and ephexin1 is significantly reduced in Cdk5 -/-brains and that Cdk5-dependent phosphorylation of ephexin1 is required for ephrin-A1-mediated regulation of spine density.These findings suggest that ephrin-A1 promotes EphA4-dependent spine retraction through the activation of Cdk5 and ephexin1 which in turn modulates actin cytoskeletal dynamics.3

Alzheimer's disease (AD) is a devastating condition with no known effective treatment. AD is characterized by memory loss as well as impaired locomotor ability, reasoning, and judgment. Emerging evidence suggests that the innate immune response plays a major role in the pathogenesis of AD. In AD, the accumulation of β-amyloid (Aβ) in the brain perturbs physiological functions of the brain, including synaptic and neuronal dysfunction, microglial activation, and neuronal loss. Serum levels of soluble ST2 (sST2), a decoy receptor for interleukin (IL)-33, increase in patients with mild cognitive impairment, suggesting that impaired IL-33/ST2 signaling may contribute to the pathogenesis of AD. Therefore, we investigated the potential therapeutic role of IL-33 in AD, using transgenic mouse models. Here we report that IL-33 administration reverses synaptic plasticity impairment and memory deficits in APP/PS1 mice. IL-33 administration reduces soluble Aβ levels and amyloid plaque deposition by promoting the recruitment and Aβ phagocytic activity of microglia; this is mediated by ST2/p38 signaling activation. Furthermore, IL-33 injection modulates the innate immune response by polarizing microglia/macrophages toward an antiinflammatory phenotype and reducing the expression of proinflammatory genes, including IL-1β, IL-6, and NLRP3, in the cortices of APP/PS1 mice. Collectively, our results demonstrate a potential therapeutic role for IL-33 in AD.innate immunity | synaptic plasticity | β-amyloid | microglia | neuroninflammation

Homeostatic plasticity is crucial for maintaining neuronal output by counteracting unrestrained changes in synaptic strength. Chronic elevation of synaptic activity by bicuculline reduces the amplitude of miniature excitatory postsynaptic currents (mEPSCs), but the underlying mechanisms of this effect remain unclear. We found that activation of EphA4 resulted in a decrease in synaptic and surface GluR1 and attenuated mEPSC amplitude through a degradation pathway that requires the ubiquitin proteasome system (UPS). Elevated synaptic activity resulted in increased tyrosine phosphorylation of EphA4, which associated with the ubiquitin ligase anaphase-promoting complex (APC) and its activator Cdh1 in neurons in a ligand-dependent manner. APC(Cdh1) interacted with and targeted GluR1 for proteasomal degradation in vitro, whereas depletion of Cdh1 in neurons abolished the EphA4-dependent downregulation of GluR1. Knockdown of EphA4 or Cdh1 prevented the reduction in mEPSC amplitude in neurons that was a result of chronic elevated activity. Our results define a mechanism by which EphA4 regulates homeostatic plasticity through an APC(Cdh1)-dependent degradation pathway.