28 research outputs found

    Cdk5 Is Required for Memory Function and Hippocampal Plasticity via the cAMP Signaling Pathway

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    Memory formation is modulated by pre- and post-synaptic signaling events in neurons. The neuronal protein kinase Cyclin-Dependent Kinase 5 (Cdk5) phosphorylates a variety of synaptic substrates and is implicated in memory formation. It has also been shown to play a role in homeostatic regulation of synaptic plasticity in cultured neurons. Surprisingly, we found that Cdk5 loss of function in hippocampal circuits results in severe impairments in memory formation and retrieval. Moreover, Cdk5 loss of function in the hippocampus disrupts cAMP signaling due to an aberrant increase in phosphodiesterase (PDE) proteins. Dysregulation of cAMP is associated with defective CREB phosphorylation and disrupted composition of synaptic proteins in Cdk5-deficient mice. Rolipram, a PDE4 inhibitor that prevents cAMP depletion, restores synaptic plasticity and memory formation in Cdk5-deficient mice. Collectively, our results demonstrate a critical role for Cdk5 in the regulation of cAMP-mediated hippocampal functions essential for synaptic plasticity and memory formation.Norman B. Leventhal FellowshipUnited States. National Institutes of Health (NIH T32 MH074249)United States. National Institutes of Health (NIH RO1 NS051874

    The concentration-dependent effects of ethanol on Caenorhabditis elegans behaviour

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    The effects of ethanol on the brain are concentration dependent. Low concentrations (mM) intoxicate, while greater than 100 mM anaesthetize. Of most relevance to human alcohol addiction are mechanisms of intoxication. Previously, Caenorhabditis elegans has been employed in genetic screens to define effectors of intoxication. Here, we inform interpretation of these studies by providing evidence that ethanol rapidly equilibriates across C. elegans cuticle. Importantly, the effect of ethanol on muscle activity rapidly reaches steady-state, and the concentration-dependence of the effect is very similar in intact animals and exposed muscle. Thus the cuticle does not present an absorption barrier for ethanol, and furthermore the internal concentration is likely to approach that applied externally. Thus, modelling intoxication in C. elegans requires exposure to external ethanol less than 100 mM. Furthermore, the permeability of the cuticle to ethanol enables analysis of precisely controlled concentration-dependent effects of acute, chronic, and episodic ethanol exposure on behaviour.<br/

    Esophageal Reflux Disease Before and After Bariatric Surgery

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    Obesity increases the risk of various weight-related disorders, including esophageal reflux disease. In this chapter, we complete a focused review of GERD before and after bariatric surgery. We will discuss the prevalence and pathophysiology of reflux in bariatric surgery patients. The rationale and management of reflux before bariatric surgery will also be addressed including surgical options such as fundoplication and the various bariatric surgery procedures that can improve reflux disease. Finally, we will discuss anti-reflux treatment options after weight loss surgery, in particular conversion from sleeve gastrectomy to Roux-en-Y gastric bypass (RYGB), placement of LINX, as well as fundoplication after sleeve gastrectomy and RYGB
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