In Noonan Syndrome (NS) 30% to 50% of subjects show cognitive deficits of unknown etiology and with no known treatment. Here, we report that knock-in mice expressing either of two NS-associated Ptpn11 mutations show hippocampal-dependent spatial learning impairments and deficits in hippocampal long-term potentiation (LTP). In addition, viral overexpression of the PTPN11D61G in adult hippocampus results in increased baseline excitatory synaptic function, deficits in LTP and spatial learning, which can all be reversed by a MEK inhibitor. Furthermore, brief treatment with lovastatin reduces Ras-Erk activation in the brain, and normalizes the LTP and learning deficits in adult Ptpn11D61G/+ mice. Our results demonstrate that increased basal Erk activity and corresponding baseline increases in excitatory synaptic function are responsible for the LTP impairments and, consequently, the learning deficits in mouse models of NS. These data also suggest that lovastatin or MEK inhibitors may be useful for treating the cognitive deficits in NS.

SummaryTo determine the effect of Helicobacter pylori CagA expression on interleukin-8 (IL-8) induction in AGS cells, cagA and five of its fragments from strains 147A and 147C that vary in the 3 ′ ′ ′ ′ repeat region were cloned into the eukaryotic expression plasmid pSP65SR α α α α . IL-8, but not RANTES or IL-I β β β β , levels were increased in AGS cells transfected with 147A-cagA and to a greater extent with 147C-cagA , compared with negative controls. The 5 ′ ′ ′ ′ b fragment from the two strains had similar effects, but the 3 ′ ′ ′ ′ d and e fragments from 147C CagA had greater effects than those from 147A-CagA. When the Western CagA-specific sequence (WSS) of 147C-cagA was replaced with East Asian CagA-specific sequence (ESS) and cloned into pSP65SR α α α α as an East/West chimera, there was no significant effect on IL-8 production. Use of specific inhibitors indicates that Src kinase activation, and the mitogen-activated protein (MAP) kinase and NF-κ κ κ κ B pathways are the major intermediates for CagA effects on IL-8 induction, but the p38 MAP kinase pathway has little effect. These results indicate a direct CagA effect on IL-8 induction by gastric epithelial cells, and indicate signal pathway loci that can be targeted for amelioration.

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In the marine mollusk Aplysia, the CCAAT/enhancer-binding protein, ApC/EBP, serves as an immediate early gene in the consolidation of long-term facilitation in the synaptic connection between the sensory and motor neurons of the gill-withdrawal reflex. To further examine the role of ApC/EBP as a molecular switch of a stable form of long-term memory, we cloned the full-length coding regions of two alternatively spliced forms, the short and long form of ApC/EBP. Overexpression of each isoform by DNA microinjection resulted in a l6-fold increase in the expression of the coinjected luciferase reporter gene driven by an ERE promoter. In addition, when we overexpressed ApC/EBP in Aplysia sensory neurons, we found that the application of a single pulse of 5-HT that normally induced only short-term facilitation now induced long-term facilitation. Conversely, when we attempted to block the synthesis of native ApC/EBP by microinjecting double-strand RNA or antisense RNA, we blocked long-term facilitation in a sequence-specific manner. These data support the idea that ApC/EBP is both necessary and sufficient to consolidate short-term memory into long-term memory. Furthermore, our results suggest that this double-strand RNA interference provides a powerful tool in the study of the genes functioning in learning and memory in Aplysia by specifically inhibiting both the constitutive and induced expression of the genes.

Short-term behavioral sensitization of the gill-withdrawal reflex after tail stimuli in Aplysia leads to an enhancement of the connections between sensory and motor neurons of this reflex. Both behavioral sensitization and enhancement of the connection between sensory and motor neurons are importantly mediated by serotonin. Serotonin activates two types of receptors in the sensory neurons, one of which is coupled to the cAMP͞protein kinase A (PKA) pathway and the other to the inositol triphosphate͞ protein kinase C (PKC) pathway. Here we describe a genetic approach to assessing the isolated contribution of the PKA pathway to short-term facilitation. We have cloned from Aplysia an octopamine receptor gene, Ap oa1, that couples selectively to the cAMP͞PKA pathway. We have ectopically expressed this receptor in Aplysia sensory neurons of the pleural ganglia, where it is not normally expressed. Activation of this receptor by octopamine stimulates all four presynaptic events involved in short-term synaptic facilitation that are normally produced by serotonin: (i) membrane depolarization; (ii) increased membrane excitability; (iii) increased spike duration; and (iv) presynaptic facilitation. These results indicate that the cAMP͞PKA pathway alone is sufficient to produce all the features of presynaptic facilitation.