TOPシンポジウム
 
阪本シンポジウム23
Sakamoto symposium -神経疾患メカニズム研究の新しい展開 -Supported by阪本精神疾患研究財団
S23-1
Brain glycosaminoglycans and their implications in neurological disorders
Irie Fumitoshi
Genetic Disease Program, Sanford-Burnham Medical Research Institute, CA, USA

Glycosaminoglycans(GAGs), such as heparan sulfate, chondroitin sulfate and hyaluronan, are liner polysaccharides present in the extracellular space and involved in many biological processes. In the nervous system, GAGs play important roles in brain development, axon guidance and synaptic function. However roles of GAGs in neurophysiology and their physiological relevance to human neurological disorders are poorly understood. In this session, I will talk about two topics,"heparan sulfate in autism"and"hyaluronan in seizure"from our recent publications. Heparan sulfate is a sulfated GAG and forms heparan sulfate proteoglycan by covalently attaching to various core proteins. Some genes encoding enzymes for heparan sulfate synthesis and core proteins are associated with mental disorders including autism. We demonstrated that elimination of heparan sulfate in postnatal neurons causes autism-like social impairments and stereotyped repetitive behaviors in mice(Irie et al. 2012). I will show behavioral phenotypes in heparan sulfate-deficient mice and potential mechanism underlying defects of brain activities. Hyaluronan, a non-sulfated GAG, is a major constituent of brain extracellular matrix in adult brain. Recently, we found that knockout mice of Has3 gene encoding one of the hyaluronan synthase show significant reduction of extracellular space in CA1 stratum pyramidale and epileptic seizures(Arranz et al. 2014). I will discuss physiological significance of hyaluronan in extracellular space volume and a causal link to epileptiform activity.
References:Irie et al. (2012)Autism-like socio-communicative deficits and stereotypies in mice lacking heparan sulfate. Proc. Natl. Acad. Sci. USA 109:5052-5056.
Arranz et al. (2014)Hyaluronan deficiency due to Has3 knock-out causes altered neuronal activity and seizures via reduction in brain extracellular space. J. Neurosci. 34:6164-6176.
S23-2
Regulation of anxiety and fear by extracellular proteolysis in the amygdala
Pawlak Robert
Functional Cell Biology, University of Exeter Medical School, Exeter, UK

It is well-established that stress can trigger maladaptive forms of neuronal plasticity and lead to high anxiety. Anxiety disorders, in their whole diversity, affect about 25% of adults at least once in their lives. Such a high prevalence of anxiety disorders, combined with high co-morbidity with depression, generates an enormous personal, social and economic burden.
Extracellular proteases such as the tissue plasminogen activator, plasmin or neuropsin are uniquely poised to remodel the neuron-extracellular matrix interface and may facilitate fear and anxiety. Two important groups of molecules that are subject to modulation by extracellular proteases are Eph-receptor tyrosine kinases and protease-activated receptors, such as PAR-1. Both groups are enriched in highly plastic areas of the brain, such as the amygdala and the hippocampus, where they promote neuronal plasticity and modulate animal's behavior.
Neuropsin(KLK8)is a kallikrein-like serine protease highly expressed in the amygdala and hippocampus. We found that upon stress neuropsin promotes stress-related anxiety in the amygdala by increasing the dynamics of EphB2/NMDA interaction that drives the expression of an anxiety-related gene, Fkbp5. Consistent with this finding;neuropsin-deficient mice do not show stress-related EphB2 cleavage, induction of the Fkbp5 gene and stress-induced anxiety.
On the other hand we found, that PAR-1 can either promote fear or protect from it depending on the previous"emotional history"of an animal by dynamically switching its coupling to distinct G-protein coupling partners.
Our findings established novel neuronal mechanisms linking stress-induced proteolysis in the amygdala to anxiety. These novel pathways open new possibilities for treatment of stress-associated disorders, including various forms of anxiety disorders.
S23-3
Activity-dependent gene expression in health and diseases
Bito Haruhiko
Department of Neurochemistry, The University of Tokyo Graduate School of Medicine

Expression and consolidation of long-term plasticity requires a complex coordination of signaling pathways to enable specific storage of otherwise transient information. How does such conversion from labile into a more stable information occur? We will here present our recent findings on multiple levels of signal cooperation, at the synaptic, dendritic and nuclear compartments of a neuron, which together contribute to achieving this formidable signal processing, especially during learning and memory. Recent human genome sequencing studies indicate that maladaptation of such signaling cascade may underlie several forms of neuropsychiatric disabilities.
References:Kawashima et al. PNAS 2009;Bito, Nature Chem Biol. 2010;Tse et al. Science 2011;Okuno et al, Cell 2012;Fujii et al. Cell Reports 2013;Kawashima et al. Nature Methods 2013;Vousden et al. Brain Struc Func. 2014;Nonaka et al. Philos Trans R Soc Lond B 2014.
S23-4
Memory as a new therapeutic target for psychopathologies
Nader Karim
Department of Psychology, McGill University

Memory retrieval is considered to have roles in memory enhancement. Recently, memory reconsolidation was suggested to reinforce or integrate new information into reactivated memory. Here, we show that reactivated inhibitory avoidance(IA)memory is enhanced through reconsolidation under conditions in which memory extinction is not induced. This memory enhancement is mediated by neurons in the amygdala, hippocampus, and medial prefrontal cortex(mPFC)through the simultaneous activation of calcineurin-induced proteasome-dependent protein degradation and cAMP responsive element binding protein-mediated gene expression. Interestingly, the amygdala is required for memory reconsolidation and enhancement, whereas the hippocampus and mPFC are required for only memory enhancement. Furthermore, memory enhancement triggered by retrieval utilizes distinct mechanisms to strengthen IA memory by additional learning that depends only on the amygdala. Our findings indicate that reconsolidation functions to strengthen the original memory and show the dynamic nature of reactivated memory through protein degradation and gene expression in multiple brain regions.