Neurofibromatosis Type I

<body topmargin=0 leftmargin=0 marginheight=0 marginwidth=0> <table cellpadding=0 cellspacing=0 border=0 height="100%"><tr> <td valign="top" width=12.5% BGCOLOR="#FFFFFF" TEXT="#080000"> <bR> </td> <td valign="top" width="100%" style=" border-top: 26px solid #FFFFFF; border-left: 63px solid #FFFFFF;border-right: 63px solid #FFFFFF;" BGCOLOR="#FFFFFF" TEXT="#080000"> <bR> <div> <TABLE BORDER="1" CELLPADDING="0" CELLSPACING="0" WIDTH="785" BORDERCOLORLIGHT="#808080" BORDERCOLORDARK="#FFFFFF" FRAME="BOX" RULES="ALL" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=TOP BGCOLOR=#DDDDDD HEIGHT= 76 ><NOBR><div> <A HREF="index.htm" TARGET="_top" TITLE="Silvalab"><B><IMG SRC="14860c470.png" border=0 width="780" height="71" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></B></A></div> </NOBR></tD> </tR> <tR> <tD VALIGN=TOP BGCOLOR=#BBBBBB HEIGHT= 30 ><NOBR><div> <B> </B><A HREF="projects.htm" TARGET="_top" TITLE="Projects "><B><IMG SRC="147e61190.png" border=0 width="97" height="25" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></B></A><A HREF="approaches.htm" TARGET="_top" TITLE="Approaches"><B><IMG SRC="147f61190.png" border=0 width="97" height="25" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></B></A><A HREF="publications.htm" TARGET="_top" TITLE="Publications"><B><IMG SRC="148061190.png" border=0 width="97" height="25" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></B></A><A HREF="personnel.htm" TARGET="_top" TITLE="Lab Members"><B><IMG SRC="148161190.png" border=0 width="97" height="25" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></B></A><A HREF="alcino.htm" TARGET="_top" TITLE="Alcino J. Silva"><B><IMG SRC="148261190.png" border=0 width="97" height="25" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></B></A><A HREF="funding.htm" TARGET="_top" TITLE="Awards"><B><IMG SRC="148361190.png" border=0 width="97" height="25" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></B></A><A HREF="positions.htm" TARGET="_top" TITLE="Open Positions"><B><IMG SRC="148461190.png" border=0 width="97" height="25" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></B></A><A HREF="aboutus.htm" TARGET="_top" TITLE="aboutus"><B><IMG SRC="148561190.png" border=0 width="97" height="25" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></B></A></div> </NOBR></tD> </tR> <tR> <tD VALIGN=TOP BGCOLOR=#6666CC HEIGHT= 20 WIDTH="781"><div>        <A HREF="index.htm" TARGET="_top" TITLE="Silvalab"><B>Home</B></A></div> </tD> </tR> </TABLE></div> <div> <TABLE BORDER="1" CELLPADDING="4" CELLSPACING="0" WIDTH="781" BORDERCOLORLIGHT="#330000" BORDERCOLORDARK="#FFFFFF" FRAME="BOX" RULES="ALL" HSPACE="0" VSPACE="0" BGCOLOR=#EEEEEE > <tR> <tD VALIGN=TOP BGCOLOR=#FFFFFF HEIGHT= 1215 WIDTH="769"><bR> <div> <B><IMG SRC="1492ff480.png" border=0 width="255" height="328" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></B></div> <div> NF1 and learning</div> <div> Specific learning disabilities are the most common neurological complication of children with Neurofibromatosis type I (NF1). The inherent complexity of these cognitive deficits, and the complications of pursuing their study in patients, motivated us to study them in mice with the same mutation that in humans causes NF1(Nf1+/- mutants).  We have showed that these mice have very specific learning deficits that have striking similarities to the deficits of children with NF1.  Our biological studies of mice with NF1 have yielded a treatment for the learning deficits in mice, and we have initiated the complex process of determining whether the same approach can cure the learning deficits of patients with NF1. </div> <div> Our work showed that Nf1+/- mutants have spatial learning deficits, but not visible-platform deficits, in the Morris water maze.  Interestingly, we have recently found that although mice with a heterozygous null mutation of the K-ras gene (K-ras+/-) also showed spatial learning deficits, the K-ras+/- mutation can rescue the spatial learning phenotype of the Nf1+/- mice. Similarly, our work also shows that either the N-ras heterozygous null mutation (N-ras+/-) or a drug that decreases Ras function (FTI or farnesyl transferase inhibitor) can also reverse the learning deficits of the Nf1+/- mutants. These results suggest that increased Ras signaling is the cause for the learning deficits in Nf1+/- mutants. </div> <bR> <div> After demonstrating that the Nf1+/- mutation affects hippocampal-dependent spatial learning, we searched for the hippocampal physiological deficits underlying the hippocampal-dependent learning abnormalities of Nf1+/- mutants. Our studies of Nf1+/- mice revealed clear deficits in long-term potentiation ( LTP; 50% reduction). LTP is a mechanism thought to be involved in learning and memory.  Unlike LTP, other aspects of hippocampal physiology were unaffected by the Nf1+/- mutation (paired-pulse facilitation, augmentation, synaptic depression, recovery from synaptic depression, probability of release measured with the MK801 method, input resistance, single-cell firing thresholds, reversal of LTP, etc.). Our studies have also uncovered the possible cause for the LTP deficits: We discovered increased GABA-mediated inhibition in these mice. Remarkably, decreasing Ras function not only rescues the learning deficits of the Nf1+/- mutants, it also rescues their increase in GABA-inhibition and the decrease in LTP. Thus, our studies indicate that the Nf1 mutation leads to increased Ras function, that this leads to increased inhibition and that the increased inhibition results in the LTP deficits that underlie their learning impairments.</div> <bR> <div> Recently, we have been able to take advantage of these findings to develop a treatment for NF1 in mice. We found that brief treatment with Lovastatin can reverse the biochemical, electrophysiological, and behavioral deficits of adult NF1 mutant mice. Currently, we are determining whether the same treatment is effective in patients. Initial findings are promising but inconclusive since we found that statin treatment improves some forms of cognitive function but perhaps not others (see recentmanuscript;  <A HREF="http://www.silvalab.com.cnchost.com/silvapapers/YpeJAMANF12008.pdf" TARGET="_top" TITLE="http://www.silvalab.com.cnchost.com/silv">PDF</A>)</div> <bR> <div> <FONT SIZE="2" COLOR="#000000" FACE="Arial" >The work described above was partially funded by NIH, but it could not have been possible without the generous help from the foundations listed below</FONT><A HREF="http://www.nf.org" TARGET="_top" TITLE="http://www.nf.org"><B><IMG SRC="0beb8160.png" border=0 width="440" height="22" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></B></A><B>        </B><A HREF="http://www.nfinc.org" TARGET="_top" TITLE="http://www.nfinc.org"><B><IMG SRC="0c0674f0.png" border=0 width="103" height="79" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></B></A></div> </tD> </tR> <tR> <tD VALIGN=TOP HEIGHT= 184 WIDTH="769"><bR> <div> For descriptions of our other projects click on one of the links below...</div> <bR> <div> <A HREF="aging.htm" TARGET="_top" TITLE="Aging and Cognition">Aging and Cognition</A>   ·   <A HREF="camkii.htm" TARGET="_top" TITLE="CaMKII and Learning">CaMKII and Learning</A>   ·   <A HREF="enhancements.htm" TARGET="_top" TITLE="Cognitive enhancements">Cognitive enhancements</A>   ·   <A HREF="cortical.htm" TARGET="_top" TITLE="Cortical memories">Cortical memories</A>   ·   <A HREF="recovery.htm" TARGET="_top" TITLE="Enhancing plasticity and recovery">Enhancing plasticity and recovery</A>   ·   <A HREF="ld.htm" TARGET="_top" TITLE="Learning disabilities">Learning disabilities</A>   ·   <A HREF="allocation.htm" TARGET="_top" TITLE="Memory Allocation">Memory Allocation</A>   ·   <A HREF="genes.htm" TARGET="_top" TITLE="Novel memory genes">Novel memory genes</A>   ·   <A HREF="schizophrenia.htm" TARGET="_top" TITLE="Schizophrenia">Schizophrenia</A>   ·   <A HREF="s2.htm" TARGET="_top" TITLE="Science of Science">Science of Science</A></div> </tD> </tR> <tR> <tD VALIGN=TOP BGCOLOR=#FFFFFF HEIGHT= 162 WIDTH="769"><bR> <bR> <bR> <bR> <div> <A HREF="projects.htm" TARGET="_top" TITLE="Projects ">Projects </A>   ·   <A HREF="approaches.htm" TARGET="_top" TITLE="Approaches">Approaches</A>   ·   <A HREF="publications.htm" TARGET="_top" TITLE="Publications">Publications</A>   ·   <A HREF="personnel.htm" TARGET="_top" TITLE="Lab Members">Lab Members</A>   ·   <A HREF="alcino.htm" TARGET="_top" TITLE="Alcino J. 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