From mTOR to cognition: molecular and cellular mechanisms of cognitive impairments in tuberous sclerosis.
BACKGROUND
Tuberous sclerosis (TSC) is a multi-system disorder caused by heterozygous mutations in the TSC1 or TSC2 gene and is often associated with neuropsychiatric symptoms, including intellectual disability, specific neuropsychological deficits, autism, other behavioural disorders and epilepsy.


METHODS
Here, we review evidence from animal models of TSC for the role of specific molecular and cellular processes in the pathogenesis of cognitive, developmental and epilepsy-related manifestations seen in the disorder.


RESULTS
Recent evidence shows that, in animal models, disinhibited mTOR (mammalian target of rapamycin) signalling substantially contributes to neuropsychiatric phenotypes, including cognitive deficits and seizures. We discuss potential pathogenetic mechanisms involved in the cognitive phenotypes of TSC and present implications regarding mTOR inhibitor-based treatments for TSC-related neuropsychiatric features.


CONCLUSIONS
Results suggest that reversing the underlying molecular deficits of TSC with rapamycin or other mTOR inhibitors could result in clinically significant improvements of cognitive function and neurological symptoms, even if treatments are started in adulthood.
Ehninger
D
D
Departments of Neurobiology, Psychiatry & Biobehavioral Sciences, Psychology and the Brain Research Institute, UCLA, Los Angeles, CA 90095-1761, USA. dehninger@mednet.ucla.edu
de Vries
P J
PJ
Silva
A J
AJ
D000818:Animals; D001522:Behavior, Animal; D002352:Carrier Proteins / Q000235:genetics*; D003585:Cell Biology; D003071:Cognition; D003072:Cognition Disorders / Q000150:complications / Q000235:genetics*; D004195:Disease Models, Animal; D004827:Epilepsy / Q000150:complications / Q000235:genetics; D006801:Humans; D051379:Mice; D008967:Molecular Biology / Q000379:methods*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D051381:Rats; D012307:Risk Factors; D058570:TOR Serine-Threonine Kinases; D014402:Tuberous Sclerosis / Q000150:complications / Q000235:genetics*
D002352:Carrier Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
Nat Rev Neurosci. 2004 Dec;5(12):931-42
15550948
J Dev Behav Pediatr. 2008 Aug;29(4):293-302
18698192
Neurobiol Dis. 2007 Nov;28(2):184-96
17714952
J Biol Chem. 2007 Sep 14;282(37):27527-27535
17635924
Nat Neurosci. 2000 Mar;3(3):211-6
10700251
Science. 2006 Oct 6;314(5796):144-8
17023663
Ann Neurol. 2008 Apr;63(4):444-53
18389497
Biochem Soc Trans. 2009 Feb;37(Pt 1):217-22
19143635
J Neurosci. 2008 May 21;28(21):5422-32
18495876
N Engl J Med. 2008 Jan 10;358(2):200-3
18184971
Nature. 2005 Aug 25;436(7054):1166-73
16121183
Genes Dev. 2008 Sep 15;22(18):2485-95
18794346
Am J Med Genet A. 2009 Mar;149A(3):387-95
19215038
J Biol Chem. 2006 Mar 31;281(13):8313-6
16464865
J Biol Chem. 2005 Nov 18;280(46):38121-4
16183639
Nat Neurosci. 2009 Feb;12(2):116-8
19151711
J Neurobiol. 2005 Jul;64(1):116-31
15883999
J Neurosci. 2005 Oct 19;25(42):9581-90
16237163
Cereb Cortex. 2007 Feb;17(2):261-71
16603714
Ann N Y Acad Sci. 1991;615:125-7
2039137
Lancet. 2008 Aug 23;372(9639):657-68
18722871
Epilepsy Behav. 2008 Nov;13(4):650-3
18703161
Epilepsia. 2005 Dec;46(12):1871-80
16393152
Epilepsy Behav. 2007 May;10(3):402-6
17392032
Trends Mol Med. 2007 Aug;13(8):319-26
17632034
Eur J Neurosci. 2006 Feb;23(3):686-92
16487150
Hum Mol Genet. 2005 Oct 15;14 Spec No. 2:R251-8
16244323
Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8573-8
15937108
Trends Neurosci. 2008 Jul;31(7):361-70
18538868
Epilepsia. 2007 Aug;48(8):1470-6
17484760
Neuron. 2007 Dec 20;56(6):955-62
18093519
Ann Neurol. 2007 Dec;62(6):648-55
18067135
Biochim Biophys Acta. 2008 Jan;1784(1):116-32
17913600
Psychol Med. 2003 Feb;33(2):335-44
12622312
Neurosci Lett. 2006 Jun 19;401(1-2):35-9
16677760
Neuron. 2009 Jan 15;61(1):10-26
19146809
J Clin Invest. 2003 Oct;112(8):1223-33
14561707
Nat Neurosci. 2005 Dec;8(12):1727-34
16286931
Neuron. 2008 Dec 26;60(6):950-60
19109903
Genomics. 2001 Dec;78(3):108-12
11735216
J Autism Dev Disord. 1998 Oct;28(5):407-14
9813776
J Clin Invest. 1999 Sep;104(6):687-95
10491404
Nature. 1997 Jun 26;387(6636):869-75
9202119
J Biol Chem. 2003 May 2;278(18):15641-51
12594228
Eur J Neurosci. 2001 Aug;14(3):547-53
11553304
Nat Neurosci. 2004 Feb;7(2):126-35
14730307
Epilepsy Behav. 2007 Dec;11(4):506-13
17936687
Am J Hum Genet. 2002 Oct;71(4):750-8
12192641
J Cell Biol. 2004 Jul 19;166(2):213-23
15249583
Mol Cell Biol. 2002 Aug;22(15):5575-84
12101249
Int J Oncol. 2004 Jan;24(1):75-80
14654943
Nat Med. 2008 Aug;14(8):843-8
18568033
J Child Neurol. 2004 Sep;19(9):666-74
15563012
Neurology. 2007 Jan 2;68(1):62-4
17200495
Curr Top Microbiol Immunol. 2004;279:169-97
14560958
Mol Cell Biol. 2008 Jun;28(12):4104-15
18411301
Am J Med Genet. 1999 Dec 15;88(6):642-6
10581483
Neuron. 2004 Sep 30;44(1):59-73
15450160
Cell. 2007 Apr 6;129(1):195-206
17418795
J Biol Chem. 2006 Jul 7;281(27):18802-15
16651266
Nat Cell Biol. 2000 May;2(5):281-7
10806479
J Med Genet. 2009 Apr;46(4):266-71
19126569
Oncogene. 2000 Dec 14;19(54):6306-16
11175345
Hum Mol Genet. 2002 Mar 1;11(5):525-34
11875047
J Neurosci. 2007 May 23;27(21):5546-58
17522300
Nat Cell Biol. 2002 Sep;4(9):648-57
12172553
J Neurosci. 2004 Nov 3;24(44):9760-9
15525761
J Child Neurol. 2004 Sep;19(9):658-65
15563011
Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13796-801
11707573
Cell. 2003 Nov 26;115(5):577-90
14651849
Mol Cell. 2008 Mar 14;29(5):541-51
18342602
Ann Neurol. 2002 Sep;52(3):285-96
12205640
Eur Child Adolesc Psychiatry. 2005 Jul;14(4):183-90
15981129
J Neurosci. 2005 Dec 7;25(49):11300-12
16339025
Curr Biol. 2004 Sep 21;14(18):1650-6
15380067
Ann Neurol. 2006 Mar;59(3):490-8
16453317
Hum Mol Genet. 2009 Apr 1;18(7):1252-65
19150975
Neurobiol Dis. 2008 Jul;31(1):127-32
18571098
Science. 2007 Feb 23;315(5815):1143-7
17289941
Mol Cell. 2006 Apr 21;22(2):159-68
16603397
Neuroreport. 1998 Aug 24;9(12):2727-31
9760110
J Autism Dev Disord. 2003 Aug;33(4):365-82
12959416
Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4430-4
9114006
Cell. 1993 Dec 31;75(7):1305-15
8269512
N Engl J Med. 2007 Jan 4;356(1):92; author reply 93-4
17202464
J Biol Chem. 2003 Sep 26;278(39):37288-96
12867426
N Engl J Med. 2006 Sep 28;355(13):1345-56
17005952
J Neurosci. 2005 Dec 7;25(49):11288-99
16339024
Dev Med Child Neurol. 1996 Feb;38(2):146-55
8603782
J Child Neurol. 2006 Feb;21(2):99-105
16566871
Brain. 2002 Jun;125(Pt 6):1247-55
12023313
Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):467-72
11756682
Ann Neurol. 2003 Aug;54(2):251-6
12891680
Ann Neurol. 2007 Feb;61(2):139-52
17279540
Science. 2005 Feb 18;307(5712):1098-101
15718470
J Neurochem. 2006 Jan;96(2):407-13
16300636
Acta Neuropathol. 2001 Mar;101(3):202-10
11307618
Neuron. 2005 Mar 3;45(5):753-64
15748850
Science. 1997 Aug 8;277(5327):805-8
9242607
J Intellect Disabil Res. 2006 Aug;50(Pt 8):561-9
16867063
Mol Cell. 2002 Jul;10(1):151-62
12150915
N Engl J Med. 2008 Jan 10;358(2):140-51
18184959
Cell. 2005 Apr 22;121(2):179-93
15851026
Nat Neurosci. 2008 Oct;11(10):1143-5
18776892
Arch Dis Child. 2004 Jun;89(6):530-3
15155396