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  • Subjects In light of several reports of defects


    In light of several reports of defects in memory-related tasks for the dysbindin-deficient mice (Cox et al., 2009, Takao et al., 2008), it was rather unexpected that an enhancement of CA3–CA1 LTP was observed in our investigation as well as in another independent study (T.T. Tang et al., 2009). The relationship between LTP and learning and memory is, however, not always strictly correlative since several mice mutants with enhanced LTP display impairments in memory-related behavior (Meng et al., 2002, Migaud et al., 1998, Uetani et al., 2000). Clinical features of schizophrenia include the positive symptoms of psychosis involving hallucinations and delusions. An association between a DTNBP1 gene variant and early-onset psychosis has been reported (Fatjo-Vilas et al., 2011). It was theorized that psychosis could be mediated by the inappropriate encoding of memories due to a mechanism involving enhanced synaptic transmission along an altered hippocampal excitatory pathway (Tamminga et al., 2010). Based on the data described here, we propose that loss of dysbindin may contribute to inappropriate memory encoding by alterations in AMPAR-mediated transmission and plasticity.
    Experimental methods
    Financial disclosures
    Acknowledgments We thank Dr. R Swank for acquisition of the sandy mice and to Dr. L Role, Dr. D Sulzer, Dr. G DiPaolo, Dr. A Yamamoto and fellow lab members for their critical input during the entire course of this study. Part of this work was presented in a poster at the 2010 Society for Neuroscience Meeting. This work was financed by grants from the National Institute of Health awarded to OA (NIH-NS049442) and a pre-doctoral NRSA training fellowship awarded to IO.
    Introduction Hepatic encephalopathy (HE) is the most common neuropsychiatric complication of liver failure. The pathophysiology of HE appears just as complex as its spectrum of clinical symptoms and signs (Aldridge et al., 2015, Butterworth, 2015, Häussinger and Schliess, 2008). Therefore, HE is no longer viewed as a single syndrome: different types of liver disease, i. e. acute versus chronic liver failure, result in different alterations of Subjects function that seem to be mediated by different mechanisms and might also require different treatment regimens (Felipo, 2013). There is general consensus, however, that hyperammonemia and inflammation play a central and synergistic role among other associated pathogenic factors (Albrecht et al., 2010, Coltart et al., 2013, Desjardins et al., 2012, Rose, 2012). Ammonia forms as a general waste product of protein metabolism. It accumulates when liver function deteriorates, readily crosses the blood–brain-barrier into brain tissue, where it rapidly exceeds the capacity of astrocytes to remove it by synthesizing glutamine, and finally becomes neurotoxic. Animal models of hyperammonemia reproduce many of the clinically observed symptoms including cognitive dysfunctions (Butterworth et al., 2009). Models of portocaval shunting and toxic liver cirrhosis, for instance, exhibited impairments in associative learning and spatial memory (Mendez et al., 2009, Mendez et al., 2011, Mendez et al., 2008, Wesierska et al., 2006), and dietary hyperammonemia constrained learning of avoidance and conditional discrimination behavior (Aguilar et al., 2000). Long-lasting, activity-dependent changes in the efficacy of synaptic neurotransmission are the leading experimental models for the capability of the brain to learn and memorize information (Bliss and Collingridge, 1993). Multiple forms of synaptic plasticity exist in the brain, with the electrophysiological phenomena of associative long-term potentiation (LTP) and long-term depression (LTD) being among the best studied (Lee and Kirkwood, 2011, Malenka and Bear, 2004). Irrespective of the great number of signal transduction pathways being activated in LTP and LTD, the strength of a glutamatergic synapse is eventually determined and varied by the number and the biophysical properties of AMPA-type glutamate receptors (AMPARs) in the postsynaptic membrane (Kessels and Malinow, 2009, Malenka and Nicoll, 1999, Malinow and Malenka, 2002, Shepherd and Huganir, 2007). Native AMPARs are formed as complexes of the pore-lining GluA1-4 subunits and accessory proteins shaping the receptors' gating properties and subcellular trafficking (Jackson and Nicoll, 2011). Co-assembly with members of the transmembrane AMPAR regulatory protein (TARP) family enhances surface expression and synaptic targeting of the receptors by direct interaction with the postsynaptic scaffolding protein PSD-95 (Tomita et al., 2003). In addition, most TARPs augment charge transfer through AMPARs as they slow channel deactivation and desensitization, increase ligand affinity, and reduce current rectification (Kato et al., 2010, Milstein and Nicoll, 2008). Besides the TARPs, also the cornichon homologs, CNIH2 and CNIH3, promote cell surface expression of AMPARs and slow their deactivation and desensitization kinetics (Schwenk et al., 2009). Several other complex constituents of native AMPARs have recently been identified in sophisticated proteomic analyses (Schwenk et al., 2012); however, TARPs and CNIHs Subjects appear to be the predominant auxiliary subunits interacting with the majority of AMPARs in the mammalian brain. Whereas their significance in shaping the gating properties of native AMPARs is indisputable, a specific role and mode of action of both TARPs and CNIHs in synaptic plasticity is still uncertain (Herring et al., 2013, Rouach et al., 2005, Sumioka et al., 2011).