TSC

<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"> <div> <TABLE BORDER="1" CELLPADDING="0" CELLSPACING="0" WIDTH="885" BORDERCOLORLIGHT="#808080" BORDERCOLORDARK="#FFFFFF" FRAME="BOX" RULES="ALL" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=TOP BGCOLOR=#DDDDDD HEIGHT= 88 ><NOBR><div> <B><IMG SRC="14d61e4a0.png" border=0 width="798" height="74" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"><IMG SRC="152953530.jpg" border=0 width="83" height="83" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></B></div> </NOBR></tD> </tR> <tR> <tD VALIGN=TOP BGCOLOR=#BBBBBB HEIGHT= 30 ><NOBR><div> <A HREF="index.htm" TARGET="_top" TITLE="Silvalab"><B> <IMG SRC="154761190.png" border=0 width="97" height="25" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></B></A><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="awards.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="881"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="881" HSPACE="0" VSPACE="0"></tD> </tR> </TABLE></div> <div> <TABLE BORDER="1" CELLPADDING="4" CELLSPACING="0" WIDTH="883" BORDERCOLORLIGHT="#330000" BORDERCOLORDARK="#FFFFFF" FRAME="BOX" RULES="ALL" HSPACE="0" VSPACE="0" BGCOLOR=#EEEEEE > <tR> <tD VALIGN=TOP BGCOLOR=#FFFFFF HEIGHT= 310 WIDTH="237"><div> Projects:</div> <bR> <div> <A HREF="aging.htm" TARGET="_top" TITLE="Aging and Cognition"><B>Aging and Cognition</B></A></div> <div> <A HREF="camkii.htm" TARGET="_top" TITLE="CaMKII and learning"><B>CaMKII and learning</B></A></div> <div> <A HREF="enhancements.htm" TARGET="_top" TITLE="Cognitive enhancements"><B>Cognitive enhancements</B></A></div> <div> <A HREF="cortical.htm" TARGET="_top" TITLE="Cortical memories"><B>Cortical memories</B></A></div> <div> <A HREF="recovery.htm" TARGET="_top" TITLE="Enhancing plasticity and recovery"><B>Enhancing plasticity and recovery</B></A></div> <div> <A HREF="disabilities.htm" TARGET="_top" TITLE="Learning disabilities"><B>Learning disabilities</B></A></div> <div> <A HREF="allocation.htm" TARGET="_top" TITLE="Memory allocation"><B>Memory allocation</B></A></div> <div> <A HREF="genes.htm" TARGET="_top" TITLE="Novel memory genes"><B>Novel memory genes</B></A></div> <div> <A HREF="schizophrenia.htm" TARGET="_top" TITLE="Schizophrenia"><B>Schizophrenia</B></A></div> <div> <A HREF="s2.htm" TARGET="_top" TITLE="Science of Science"><B>Science of Science</B></A></div> <bR> <div> <A HREF="nf1.htm" TARGET="_top" TITLE="Neurofibromatosis Type I"><B>Our NF1 work </B></A></div> </tD> <tD VALIGN=TOP BGCOLOR=#FFFFFF WIDTH="624"><bR> <div> <B><IMG SRC="1525d6130.jpg" border=0 width="214" height="275" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></B></div> </tD> </tR> <tR> <tD VALIGN=TOP COLSPAN=2 BGCOLOR=#FFFFFF HEIGHT= 450 WIDTH="863"><div> Tuberous Sclerosis</div> <div> <B>Tuberous sclerosis (TSC) is a single-gene disorder caused by heterozygous mutations in the TSC1 (9q34) or TSC2 (16p13.3) gene, and is frequently associated with mental retardation, autism and epilepsy. Even TSC individuals with a normal IQ (approximately 50%) are commonly affected with specific neuropsychological problems, including long-term and working memory deficits.  We have demonstrated that mice with a heterozygous, inactivating mutation in the Tsc2 gene (Tsc2+/- mice) have deficits in learning and memory. Cognitive deficits in Tsc2+/- mice emerge in the absence of neuropathology and seizures, demonstrating that other disease mechanisms are involved. We show that in these mice hyperactive hippocampal mTOR signaling leads to abnormal hippocampal CA1 LTP and consequently to deficits in hippocampal-dependent learning. These deficits include impairments in two spatial learning tasks, and in contextual discrimination. Remarkably, we demonstrated that a brief treatment with the mTOR inhibitor rapamycin in adult mice can rescue not only the synaptic plasticity, but also the behavioral deficits in this animal model of TSC. Our results reveal a biological basis for some of the cognitive deficits associated with TSC and they show that treatment with mTOR antagonists ameliorates cognitive dysfunction in a mouse model of this disorder. We are currently involved in a collaboration to determine if the same treatment is efective in TSC patients.</B></div> <bR> <div> <A HREF="http://www.tsalliance.org/" TARGET="_top" TITLE="http://www.tsalliance.org/"><B><IMG SRC="12438b660.jpg" border=0 width="139" height="102" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></B></A></div> </tD> </tR> <tR> <tD VALIGN=TOP COLSPAN=2 BGCOLOR=#FFFFFF HEIGHT= 142 WIDTH="863"><div> Key Publication:</div> <bR> <div> <FONT SIZE="2" COLOR="#000000" FACE="Calibri" ><B>Ehninger, D., S. Han, C. Shilyansky, Y. Zhou, W. Li, D.J. Kwiatkowski, V. Ramesh, and A.J. Silva, Reversal of learning deficits in a Tsc2(+/-) mouse model of tuberous sclerosis. Nat Med, 2008.</B></FONT><B>(</B><A HREF="http://www.silvalab.com.cnchost.com/silvapapers/DanNM2008.pdf" TARGET="_top" TITLE="http://www.silvalab.com.cnchost.com/silv"><B>Click Here</B></A><B>)</B></div> </tD> </tR> <tR> <tD VALIGN=TOP COLSPAN=2 BGCOLOR=#FFFFFF HEIGHT= 103 WIDTH="863"><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. Silva">Alcino J. 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