Domain contributions to signaling specificity differences between Ras-guanine nucleotide releasing factor (Ras-GRF) 1 and Ras-GRF2.

Ras-GRF1 (GRF1) and Ras-GRF2 (GRF2) constitute a family of similar calcium sensors that regulate synaptic plasticity. They are both guanine exchange factors that contain a very similar set of functional domains, including N-terminal pleckstrin homology, coiled-coil, and calmodulin-binding IQ domains and C-terminal Dbl homology Rac-activating domains, Ras-exchange motifs, and CDC25 Ras-activating domains. Nevertheless, they regulate different forms of synaptic plasticity. Although both GRF proteins transduce calcium signals emanating from NMDA-type glutamate receptors in the CA1 region of the hippocampus, GRF1 promotes LTD, whereas GRF2 promotes θ-burst stimulation-induced LTP (TBS-LTP). GRF1 can also mediate high frequency stimulation-induced LTP (HFS-LTP) in mice over 2-months of age, which involves calcium-permeable AMPA-type glutamate receptors. To add to our understanding of how proteins with similar domains can have different functions, WT and various chimeras between GRF1 and GRF2 proteins were tested for their abilities to reconstitute defective LTP and/or LTD in the CA1 hippocampus of Grf1/Grf2 double knock-out mice. These studies revealed a critical role for the GRF2 CDC25 domain in the induction of TBS-LTP by GRF proteins. In contrast, the N-terminal pleckstrin homology and/or coiled-coil domains of GRF1 are key to the induction of HFS-LTP by GRF proteins. Finally, the IQ motif of GRF1 determines whether a GRF protein can induce LTD. Overall, these findings show that for the three forms of synaptic plasticity that are regulated by GRF proteins in the CA1 hippocampus, specificity is encoded in only one or two domains, and a different set of domains for each form of synaptic plasticity.

Long-lasting and transgenerational effects of an environmental enrichment on memory formation.

It has long been believed that genetically determined, but not environmentally acquired, phenotypes can be inherited. However, a large number of recent studies have reported that phenotypes acquired from an animal's environment can be transmitted to the next generation. Moreover, epidemiology studies have hinted that a similar phenomenon occurs in humans. This type of inheritance does not involve gene mutations that change DNA sequence. Instead, it is thought that epigenetic changes in chromatin, such as DNA methylation and histone modification, occur. In this review, we will focus on one exciting new example of this phenomenon, transfer across generations of enhanced synaptic plasticity and memory formation induced by exposure to an "enriched" environment.

Sos2 is dispensable for NMDA-induced Erk activation and LTP induction.

N-methyl-d-aspartate (NMDA) receptor-induced activation of extracellular signal-related protein kinase (Erk) plays important roles in various neuronal functions including long-term potentiation (LTP). Son of sevenless (Sos) proteins have been implicated in NMDA-induced Erk activation in neurons of young mice. However, contribution of each of the two Sos isoforms, Sos1 and Sos2, has not been clarified. In this study, Sos2 involvement in NMDA-induced Erk activation was examined. We observed no defect in Erk phosphorylation induced by NMDA treatment of cortical neuronal cultures from Sos2-/- newborn mice. Moreover, theta-burst-induced LTP induction in the hippocampus of Sos2-/- mice was also normal. Finally, Erk activation by either depolarization or BDNF treatment was also normal in cultured neurons from Sos2 knockout mice. These results imply that Sos1 is the major regulator of these well-known neuronal Sos functions and suggest that a novel function for Sos2 in neurons remains to be determined.

Transgenerational rescue of a genetic defect in long-term potentiation and memory formation by juvenile enrichment.

The idea that qualities acquired from experience can be transmitted to future offspring has long been considered incompatible with current understanding of genetics. However, the recent documentation of non-Mendelian transgenerational inheritance makes such a "Lamarckian"-like phenomenon more plausible. Here, we demonstrate that exposure of 15-d-old mice to 2 weeks of an enriched environment (EE), that includes exposure to novel objects, elevated social interactions and voluntary exercise, enhances long-term potentiation (LTP) not only in these enriched mice but also in their future offspring through early adolescence, even if the offspring never experience EE. In both generations, LTP induction is augmented by a newly appearing cAMP/p38 MAP kinase-dependent signaling cascade. Strikingly, defective LTP and contextual fear conditioning memory normally associated with ras-grf knock-out mice are both masked in the offspring of enriched mutant parents. The transgenerational transmission of this effect occurs from the enriched mother to her offspring during embryogenesis. If a similar phenomenon occurs in humans, the effectiveness of one's memory during adolescence, particularly in those with defective cell signaling mechanisms that control memory, can be influenced by environmental stimulation experienced by one's mother during her youth.