Title: Reversing Neurodevelopmental Disorders in Adults
Abstract: Abnormalities in brain development, thought to be irreversible in adults, have long been assumed to underlie the neurological and psychiatric symptoms associated with neurodevelopmental disorders. Surprisingly, a number of recent animal model studies of neurodevelopmental disorders demonstrate that reversing the underlying molecular deficits can result in substantial improvements in function even if treatments are started in adulthood. These findings mark a paradigmatic change in the way we understand and envision treating neurodevelopmental disorders. Abnormalities in brain development, thought to be irreversible in adults, have long been assumed to underlie the neurological and psychiatric symptoms associated with neurodevelopmental disorders. Surprisingly, a number of recent animal model studies of neurodevelopmental disorders demonstrate that reversing the underlying molecular deficits can result in substantial improvements in function even if treatments are started in adulthood. These findings mark a paradigmatic change in the way we understand and envision treating neurodevelopmental disorders. The term “neurodevelopmental disorders” encompasses a large group of disorders that share the fact that disease onset is during periods of ongoing maturation and development. These disorders are often associated with complex neuropsychiatric features including intellectual disability, specific learning disabilities, ADHD, autism, and epilepsy, among others. Neurodevelopmental disorders are caused by a wide range of genetic mutations and environmental factors (e.g., infections, immune dysfunction, intoxication, endocrine and metabolic dysfunction, nutritional factors, trauma, etc.). Heritability estimates indicate that genetic factors play an important role in these disorders. Although our review is focused on single-gene disorders, the basic implications discussed may be more broadly relevant and therefore applicable to neurodevelopmental disorders in general. Neurodevelopmental disorders are thought to be caused by changes in development, potentially involving alterations in neurogenesis, cell migration, and neuronal connectivity that are responsible for cognitive deficits in adults. Accordingly, abnormalities in brain structure, resulting from perturbed development, are often associated with neurodevelopmental disorders. Additionally, development is an especially vulnerable period: insults with a minor impact in adults can result in significant pathologies when occurring during development. For example, absence of serotonin1A receptor function in the forebrain during postnatal development, but not in adulthood, results in anxiety-related behavioral phenotypes in mice (Gross et al., 2002Gross C. Zhuang X. Stark K. Ramboz S. Oosting R. Kirby L. Santarelli L. Beck S. Hen R. Nature. 2002; 416: 396-400Crossref PubMed Scopus (757) Google Scholar). Similarly, maternal care during early postnatal periods has been shown to influence hippocampal glucocorticoid receptor expression, stress responsiveness, and behavior in the offspring via epigenetic modulations that last into adulthood (Caldji et al., 1998Caldji C. Tannenbaum B. Sharma S. Francis D. Plotsky P.M. Meaney M.J. Proc. Natl. Acad. Sci. USA. 1998; 95: 5335-5340Crossref PubMed Scopus (1140) Google Scholar, Francis et al., 1999Francis D. Diorio J. Liu D. Meaney M.J. Science. 1999; 286: 1155-1158Crossref PubMed Scopus (1515) Google Scholar, Liu et al., 1997Liu D. Diorio J. Tannenbaum B. Caldji C. Francis D. Freedman A. Sharma S. Pearson D. Plotsky P.M. Meaney M.J. Science. 1997; 277: 1659-1662Crossref PubMed Scopus (2579) Google Scholar, Weaver et al., 2004Weaver I.C. Cervoni N. Champagne F.A. D'Alessio A.C. Sharma S. Seckl J.R. Dymov S. Szyf M. Meaney M.J. Nat. Neurosci. 2004; 7: 847-854Crossref PubMed Scopus (4591) Google Scholar). A recent study with an animal model of schizophrenia (Li et al., 2007Li W. Zhou Y. Jentsch J.D. Brown R.A. Tian X. Ehninger D. Hennah W. Peltonen L. Lonnqvist J. Huttunen M.O. et al.Proc. Natl. Acad. Sci. USA. 2007; 104: 18280-18285Crossref PubMed Scopus (186) Google Scholar) showed that a brief induction of a DISC1 mutant allele during postnatal development, but not in adults, is sufficient to trigger many of the phenotypes associated with this neurodevelopmental disorder (Weinberger, 1987Weinberger D.R. Arch. Gen. Psychiatry. 1987; 44: 660-669Crossref PubMed Scopus (3033) Google Scholar). Clinical experience with endocrine and metabolic disorders also stresses the importance of insults during vulnerable periods of development: hypothyroidism and phenylketonuria, for example, can lead to profound and irreversible cognitive disability when left uncorrected during developmental periods, while they appear to have milder effects in adults (Davis and Tremont, 2007Davis J.D. Tremont G. Minerva Endocrinol. 2007; 32: 49-65PubMed Google Scholar, Dugbartey, 1998Dugbartey A.T. Arch. Intern. Med. 1998; 158: 1413-1418Crossref PubMed Scopus (205) Google Scholar, Hanley, 2004Hanley W.B. Am. J. Med. 2004; 117: 590-595Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, Rovet and Daneman, 2003Rovet J. Daneman D. Paediatr. Drugs. 2003; 5: 141-149Crossref PubMed Scopus (91) Google Scholar, Zoeller and Rovet, 2004Zoeller R.T. Rovet J. J. Neuroendocrinol. 2004; 16: 809-818Crossref PubMed Scopus (458) Google Scholar). Nevertheless, there are many other examples of pathologies where the opposite is true: for example, trauma, infection, and ischemia may have much of the same or even more dire effects in adults than in developing organisms (Kolb et al., 2000Kolb B. Gibb R. Gorny G. Dev. Neuropsychol. 2000; 18: 423-444Crossref PubMed Scopus (79) Google Scholar, Vannucci and Hagberg, 2004Vannucci S.J. Hagberg H. J. Exp. Biol. 2004; 207: 3149-3154Crossref PubMed Scopus (367) Google Scholar). Many of the mutations that cause developmental disorders disrupt gene(s) that are also expressed in the adult brain. Thus, in addition to developmental effects on brain structure and function, it is possible that altered gene function in adulthood may contribute to associated cognitive phenotypes. Accordingly, a number of recent studies of animal models of neurodevelopmental disorders strongly suggest that adult disruption of gene function makes a significant contribution to cognitive disability and neurological dysfunction associated with these disorders. These studies demonstrate that treating the disrupted molecular and cellular mechanisms specifically in adults can result in dramatic improvements in cognitive function. It is conceivable that biochemical amelioration of the underlying genetic deficits may allow robust molecular, cellular, structural, and behavioral plasticity mechanisms in the adult brain to compensate for or even correct specific developmental pathologies. Recent studies using animal models of several single-gene developmental disorders provide compelling evidence that cognitive deficits and neurological impairments associated with neurodevelopmental disorders can be reversed, even if treatment is initiated in adults (Table 1). For example, neurofibromatosis I (NF1) is a complex developmental genetic disorder caused by mutations in the NF1 gene. Specific learning disabilities, including difficulties with visuospatial skills, memory, and attentional-executive function, are commonly associated with NF1. Mice with a heterozygous deletion of the Nf1 gene (Nf1+/− mice) displayed spatial learning deficits (Silva et al., 1997Silva A.J. Frankland P.W. Marowitz Z. Friedman E. Laszlo G.S. Cioffi D. Jacks T. Bourtchuladze R. Nat. Genet. 1997; 15: 281-284Crossref PubMed Scopus (295) Google Scholar) and impairments in attentional-executive function (Li et al., 2005Li W. Cui Y. Kushner S.A. Brown R.A. Jentsch J.D. Frankland P.W. Cannon T.D. Silva A.J. Curr. Biol. 2005; 15: 1961-1967Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar), akin to neuropsychological impairments observed in NF1 patients. The NF1 gene encodes neurofibromin, a GTPase-activating protein that accelerates the inactivation of Ras, thereby inhibiting Ras-MAPK signaling. Accordingly, loss-of-function mutations in the NF1 gene lead to disinhibited Ras-MAPK signaling, a pathway with a known role in neurodevelopment. Nf1+/− mice show defects in long-term potentiation (LTP) due to increased inhibitory neurotransmission in the hippocampus (Costa et al., 2002Costa R.M. Federov N.B. Kogan J.H. Murphy G.G. Stern J. Ohno M. Kucherlapati R. Jacks T. Silva A.J. Nature. 2002; 415: 526-530Crossref PubMed Scopus (469) Google Scholar).Table 1SyndromeNeuropsychiatric PhenotypesGenetic CauseAnimal ModelDrugTreatment DetailsRescued Phenotype(s)ReferenceNeurofibromatosis Ilearning disabilitiesheterozygous NF1 mutationsNf1+/− miceBMS 191563 (farnesyl-transferase inhibitor)adult mice, treatment concomitantly with behaviorspatial learning deficits (Morris water maze)Costa et al., 2002Costa R.M. Federov N.B. Kogan J.H. Murphy G.G. Stern J. Ohno M. Kucherlapati R. Jacks T. Silva A.J. Nature. 2002; 415: 526-530Crossref PubMed Scopus (469) Google Scholarlovastatin (HMG CoA reductase inhibitor)adult mice; treatment was initiated 3 days prior to behavior (Morris water maze)spatial learning (Morris water maze) and attention deficits (lateralized reaction time test), prepulse inhibition deficits, deficits in long-term potentiationLi et al., 2005Li W. Cui Y. Kushner S.A. Brown R.A. Jentsch J.D. Frankland P.W. Cannon T.D. Silva A.J. Curr. Biol. 2005; 15: 1961-1967Abstract Full Text Full Text PDF PubMed Scopus (325) Google ScholarDown's Syndromeintellectual disability, learning disabilities, behavior disorders, epilepsytrisomy 21Ts65Dn micepicrotoxin, pentylene-tetrazole, bilobalide (GABAA receptor antagonists)3- to 4-month-old mice; minimum effective treatment duration: 2 weeks; therapeutic effect lasted for months even if treatment was discontinuedlearning and memory deficits in object recognition task, spontaneous alternation, deficient long-term potentiationFernandez et al., 2007Fernandez F. Morishita W. Zuniga E. Nguyen J. Blank M. Malenka R.C. Garner C.C. Nat. Neurosci. 2007; 10: 411-413PubMed Google Scholarpentylene-tetrazole (GABAA receptor antagonist)7 week treatment started at 4 monthsspatial learning deficits (Morris water maze)Rueda et al., 2008Rueda N. Florez J. Martinez-Cue C. Neurosci. Lett. 2008; 433: 22-27Crossref PubMed Scopus (110) Google ScholarRubinstein-Taybi Syndromeintellectual disabilityheterozygous mutations in CBP (but genetic heterogeneity)Cbp+/− miceHT0712, rolipram (PDE-4 inhibitors)single treatment prior to behaviorlong-term memory deficit in object recognition taskBourtchouladze et al., 2003Bourtchouladze R. Lidge R. Catapano R. Stanley J. Gossweiler S. Romashko D. Scott R. Tully T. Proc. Natl. Acad. Sci. USA. 2003; 100: 10518-10522Crossref PubMed Scopus (286) Google ScholarSAHA (HDAC inhibitor)single treatment prior to behaviorlong-term memory deficit in context fear conditioning, deficient long-term potentiationAlarcon et al., 2004Alarcon J.M. Malleret G. Touzani K. Vronskaya S. Ishii S. Kandel E.R. Barco A. Neuron. 2004; 42: 947-959Abstract Full Text Full Text PDF PubMed Scopus (758) Google ScholarTuberous Sclerosisintellectual disability, learning disabilities, epilepsy, autism, behavior disordersheterozygous mutations in TSC1 or TSC2Tsc2+/− micerapamycin (mTOR inhibitor)3- to 6-month-old mice; treatment started concomitantly with behavior (Morris water maze) or 5 days prior to behavior (context discrimination)spatial learning deficits (Morris water maze), context discrimination, long-term potentiation phenotypeEhninger et al., 2008Ehninger D. Han S. Shilyansky C. Zhou Y. Li W. Kwiatkowski D.J. Ramesh V. Silva A.J. Nat. Med. 2008; 14: 843-848Crossref PubMed Scopus (667) Google Scholarneuronal homozygous Tsc1 mutant micerapamycin (mTOR inhibitor)treatment started at postnatal day 1 and was continued to adulthoodneurological findings (hindlimb clasping, hypoactivity), brain enlargement and lethalityEhninger et al., 2008Ehninger D. Han S. Shilyansky C. Zhou Y. Li W. Kwiatkowski D.J. Ramesh V. Silva A.J. Nat. Med. 2008; 14: 843-848Crossref PubMed Scopus (667) Google Scholarneuronal homozygous Tsc1 mutant micerapamycin, RAD001 (mTOR inhibitors)treatment started at postnatal day 7–9 and was continued to adulthoodneurological findings (clasping, tremor, kyphosis, abberant tail position), elevated brain/body weight ratio, impaired myelinationMeikle et al., 2008Meikle L. Pollizzi K. Egnor A. Kramvis I. Lane H. Sahin M. Kwiatkowski D.J. J. Neurosci. 2008; 28: 5422-5432Crossref PubMed Scopus (399) Google Scholarastroglial homozygous Tsc1 mutant micerapamycin (mTOR inhibitor)treatment initiated at 2 weeks (before seizure onset) or at 6 weeks of age (after seizure onset)rescue of seizures and lethality (in both treatment groups); prevention of astrogliosis and abnormal neuronal organizationZeng et al., 2008Zeng L.H. Xu L. Gutmann D.H. Wong M. Ann. Neurol. 2008; 63: 444-453Crossref PubMed Scopus (483) Google ScholarLhermitte-Duclos Disease; Cowden Disease; AutismLhermitte-Duclos disease: intellectual disability, ataxia epilepsyPTEN mutationsmice with neuronal homozygous deletion of PtenCCI-779 (mTOR inhibitor)for analysis of adult mice, treatment started when mutant mice were clearly symptomatic (ranging from 6 to 16 weeks of age); treatment for 4–8 weeksreversal of phenotypic features in symptomatic adult mice (seizures, dentate gyrus granule cell hypertrophy; lethality)Kwon et al., 2003Kwon C.H. Zhu X. Zhang J. Baker S.J. Proc. Natl. Acad. Sci. USA. 2003; 100: 12923-12928Crossref PubMed Scopus (200) Google ScholarFragile X Syndromeintellectual disability, autism, learning disabilities, behavior disorders, epilepsytriplet repeat expansion that leads to transcriptional silencing of FMR1 genefragile X drosophila model (homozygous dfmr1 mutants with a transgene containing a frameshift mutation in the dfmr1 open reading frame)MPEP, LY341495, MPPG, MTPG (mGluR antago-nists), lithium4 days treatment started in adulthood (after eclosion)naive courtship behavior (partial restoration in adult FXS flies by MPEP, LY341495, lithium, MPPG, MTPG; all drugs decreased courtship behavior in control flies), immediate recall memory (rescue in adult FXS flies by MPEP), short-term memory (rescue in adult FXS flies by MPEP, lithium, LY341495)McBride et al., 2005McBride S.M. Choi C.H. Wang Y. Liebelt D. Braunstein E. Ferreiro D. Sehgal A. Siwicki K.K. Dockendorff T.C. Nguyen H.T. et al.Neuron. 2005; 45: 753-764Abstract Full Text Full Text PDF PubMed Scopus (406) Google Scholartreatment only during development (before eclosion)naive courtship behavior, immediate recall memory, short-term memory (rescue in FXS flies by MPEP)Fmr1 mutant micegenetic rescue: Fmr1 mutant mice were crossed to heterozygous mGluR5 mutant micegermline mutation in mGluR5: gene function reduced during development and in adulthoodinhibitory avoidance extinction, audiogenic seizures, accelerated body growth, dendritic spine density, ocular dominance plasticityDolen et al., 2007Dolen G. Osterweil E. Rao B.S. Smith G.B. Auerbach B.D. Chattarji S. Bear M.F. Neuron. 2007; 56: 955-962Abstract Full Text Full Text PDF PubMed Scopus (776) Google ScholarAngelman Syndromeintellectual disability, learning disabilities, movement disorders, language impairments, epilepsy, behavioral features (hyperactivity, frequent laughter, etc.)loss-of-function of imprinted genes on chromosome 15q11-13; UBE3A mutationsheterozygous mice with a maternally inherited Ube3a mutation (Ube3ap+/m−mice)genetic rescue: Ube3ap+/m−mice were crossed to heterozygous αCaMKII-T305V/T306A mutant micerescue of Ube3ap+/m−phenotypes by αCaMKII-T305V/T306A mutation suggests that Ube3ap+/m−phenotypes emerge as a consequence of postnatal pathologyaudiogenic seizures, motor coordination deficits (accelerating rotarod), spatial learning deficits (Morris water maze), context fear conditioning deficits, increased body weight, deficient long-term potentiationvan Woerden et al., 2007van Woerden G.M. Harris K.D. Hojjati M.R. Gustin R.M. Qiu S. de Avila Freire R. Jiang Y.H. Elgersma Y. Weeber E.J. Nat. Neurosci. 2007; 10: 280-282Crossref PubMed Scopus (230) Google ScholarRett Syndromeintellectual disability, autistic features, epilepsy, motor symptoms (delay or absence of walking, ataxia, hypotonia, dystonia, chorea, spasticity)MECP2 mutationsMecp2 gene silenced by insertion of lox-STOP cassettegenetic rescue: activation of Mecp2 expression by Cre-mediated deletion of STOP cassette (Cre translocation into nucleus only in presence of tamoxifen)a series of experiments with different temporal activation of Mecp2 was performed; activation of Mecp2 after establishment of neurological symptoms reversed neurological diseaseneurological compound score (hindlimb clasping, inertia, irregular breathing, gait, tremor, poor general condition)Guy et al., 2007Guy J. Gan J. Selfridge J. Cobb S. Bird A. Science. 2007; 315: 1143-1147Crossref PubMed Scopus (876) Google Scholar Open table in a new tab Two pharmacological strategies that reduce the isoprenylation of Ras, and thereby decrease active (membrane-bound) Ras, have been used to rescue the signaling, physiology, and behavioral deficits of these mice: farnesyl-transferase inhibition with BMS 191563 (Costa et al., 2002Costa R.M. Federov N.B. Kogan J.H. Murphy G.G. Stern J. Ohno M. Kucherlapati R. Jacks T. Silva A.J. Nature. 2002; 415: 526-530Crossref PubMed Scopus (469) Google Scholar) and HMG-CoA reductase inhibition with lovastatin (Li et al., 2005Li W. Cui Y. Kushner S.A. Brown R.A. Jentsch J.D. Frankland P.W. Cannon T.D. Silva A.J. Curr. Biol. 2005; 15: 1961-1967Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar). HMG-CoA reductase is the rate-limiting enzyme in the mevalonate pathway in which isoprenyl groups (and then cholesterol) are synthesized. Notably, a short pharmacological treatment of adult mice was sufficient to decrease Ras-MAPK signaling, restore LTP, and reverse cognitive deficits in Nf1+/− mice. Drug doses sufficient to rescue the phenotypes of the mutants did not have a measurable effect on controls (Costa et al., 2002Costa R.M. Federov N.B. Kogan J.H. Murphy G.G. Stern J. Ohno M. Kucherlapati R. Jacks T. Silva A.J. Nature. 2002; 415: 526-530Crossref PubMed Scopus (469) Google Scholar, Li et al., 2005Li W. Cui Y. Kushner S.A. Brown R.A. Jentsch J.D. Frankland P.W. Cannon T.D. Silva A.J. Curr. Biol. 2005; 15: 1961-1967Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar), a result that indicates that the drugs used targeted the mechanisms disrupted in these mutants. Importantly, a recent clinical study reported that although a brief 12 week simvastatin treatment did not have a significant overall effect on the cognition of patients, it did rescue deficits in an object assembly test (Krab et al., 2008Krab L.C. de Goede-Bolder A. Aarsen F.K. Pluijm S.M. Bouman M.J. van der Geest J.N. Lequin M. Catsman C.E. Arts W.F. Kushner S.A. et al.JAMA. 2008; 300: 287-294Crossref PubMed Scopus (157) Google Scholar). Moreover, the treatment had the biggest impact on patients with the poorest performances, while not affecting the performances of patients with scores within the normal range. Although promising, longer treatments with larger sample sizes are needed to confirm that statins have a beneficial impact on the cognition of NF1 patients. Remarkably, similar to the Nf1+/− mice (Costa et al., 2002Costa R.M. Federov N.B. Kogan J.H. Murphy G.G. Stern J. Ohno M. Kucherlapati R. Jacks T. Silva A.J. Nature. 2002; 415: 526-530Crossref PubMed Scopus (469) Google Scholar), the hippocampal learning and memory deficits of an animal model of Down's syndrome (the Ts65Dn mice) appear to be due to deficits in hippocampal LTP caused by enhanced GABAergic inhibition (Kleschevnikov et al., 2004Kleschevnikov A.M. Belichenko P.V. Villar A.J. Epstein C.J. Malenka R.C. Mobley W.C. J. Neurosci. 2004; 24: 8153-8160Crossref PubMed Scopus (387) Google Scholar). Down's syndrome, caused by trisomy 21, is the most common genetic disorder associated with intellectual disability. The Ts65Dn mouse model of the disorder (Reeves et al., 1995Reeves R.H. Irving N.G. Moran T.H. Wohn A. Kitt C. Sisodia S.S. Schmidt C. Bronson R.T. Davisson M.T. Nat. Genet. 1995; 11: 177-184Crossref PubMed Scopus (755) Google Scholar) is based on the partial triplication of chromosome 16, the mouse homolog to human chromosome 21. Until recently, nearly all of the mechanistic studies of this disorder focused on the impact of genetic changes on development. A recent ground-breaking study, aimed at testing the hypothesis that abnormally high levels of inhibition in adult mice play a role in the pathogenesis of Down's syndrome-related cognitive dysfunction (Fernandez et al., 2007Fernandez F. Morishita W. Zuniga E. Nguyen J. Blank M. Malenka R.C. Garner C.C. Nat. Neurosci. 2007; 10: 411-413PubMed Google Scholar), showed that although acute treatment (1 day) with a GABAA receptor antagonist (picrotoxin) had no effect, a 2 week treatment with several GABAA receptor antagonists (picrotoxin, pentylenetetrazole, or bilobalide) rescued cognitive deficits (object recognition, spontaneous alternation) in adult Ts65Dn mice. The same treatment did not affect learning in controls, a result consistent with the idea that increased inhibition accounts for the learning and memory deficits in Ts65Dn mice. Surprisingly, an ∼2 week treatment with GABAA antagonists (Fernandez et al., 2007Fernandez F. Morishita W. Zuniga E. Nguyen J. Blank M. Malenka R.C. Garner C.C. Nat. Neurosci. 2007; 10: 411-413PubMed Google Scholar) led to a persistent (for at least up to 2 months) behavioral recovery even though the treatment was not extended beyond the initial ∼2 week period. Similarly, this treatment also resulted in the (partial) rescue of LTP, even when LTP was tested 3 months after the completion of the ∼2 week treatment. These findings have been recently confirmed and extended in a study that showed that a 7 week treatment with the GABAA receptor antagonist pentylenetetrazole also rescues spatial learning deficits in adult Ts65Dn mice (Rueda et al., 2008Rueda N. Florez J. Martinez-Cue C. Neurosci. Lett. 2008; 433: 22-27Crossref PubMed Scopus (110) Google Scholar). The results reviewed above show that reversing the increased inhibition in the Ts65Dn mutants triggered lasting adaptive changes that result in improvements in cognition. The unexpected (and unexplained) delayed therapeutic action of this treatment is reminiscent of other psychopharmacological effects, such as the well-known delayed effect of antidepressants. Could treatment with GABA receptor inhibitors, and the resulting lowering of inhibitory tone, lead to the reactivation of developmental plasticity processes (see discussion below) that contributed to the restored LTP and learning of the Ts65Dn mice? Could similar treatments reverse the cognitive deficits associated with Down's syndrome? Rubinstein-Taybi syndrome (RTS) is another genetic disorder characterized by intellectual disability and characteristic physical features that include broad thumbs and toes as well as facial abnormalities (Rubinstein and Taybi, 1963Rubinstein J.H. Taybi H. Am. J. Dis. Child. 1963; 105: 588-608Crossref PubMed Scopus (373) Google Scholar). Although there are multiple genes implicated in RTS, mutations in the CREB-binding protein (CBP) are known to cause this syndrome (Petrij et al., 1995Petrij F. Giles R.H. Dauwerse H.G. Saris J.J. Hennekam R.C. Masuno M. Tommerup N. van Ommen G.J. Goodman R.H. Peters D.J. et al.Nature. 1995; 376: 348-351Crossref PubMed Scopus (1022) Google Scholar). CBP is a transcriptional coactivator, has histone acetyltransferase activity, and is involved in transcriptional control downstream of cAMP signaling, linking experience-dependent neuronal activation to gene expression and long-term memory formation (Hallam and Bourtchouladze, 2006Hallam T.M. Bourtchouladze R. Cell. Mol. Life Sci. 2006; 63: 1725-1735Crossref PubMed Scopus (39) Google Scholar, Lonze and Ginty, 2002Lonze B.E. Ginty D.D. Neuron. 2002; 35: 605-623Abstract Full Text Full Text PDF PubMed Scopus (1739) Google Scholar). A mouse model of RTS (Cbp+/− mice) shows normal short-term memory but impaired long-term memory in context fear conditioning and object recognition (Alarcon et al., 2004Alarcon J.M. Malleret G. Touzani K. Vronskaya S. Ishii S. Kandel E.R. Barco A. Neuron. 2004; 42: 947-959Abstract Full Text Full Text PDF PubMed Scopus (758) Google Scholar, Bourtchouladze et al., 2003Bourtchouladze R. Lidge R. Catapano R. Stanley J. Gossweiler S. Romashko D. Scott R. Tully T. Proc. Natl. Acad. Sci. USA. 2003; 100: 10518-10522Crossref PubMed Scopus (286) Google Scholar). Memory deficits in Cbp+/− mice could be restored in adult mice using pharmacological strategies that enhance CREB-dependent gene expression: the HDAC inhibitor SAHA is known to promote histone acetylation, and it was shown to improve context fear memory in Cbp+/− mice (Alarcon et al., 2004Alarcon J.M. Malleret G. Touzani K. Vronskaya S. Ishii S. Kandel E.R. Barco A. Neuron. 2004; 42: 947-959Abstract Full Text Full Text PDF PubMed Scopus (758) Google Scholar). Second, phospodiesterase-4 (PDE-4) inhibitors (inhibit breakdown of cAMP) also improve long-term memory in adult Cbp+/− mice (Bourtchouladze et al., 2003Bourtchouladze R. Lidge R. Catapano R. Stanley J. Gossweiler S. Romashko D. Scott R. Tully T. Proc. Natl. Acad. Sci. USA. 2003; 100: 10518-10522Crossref PubMed Scopus (286) Google Scholar), perhaps because they enhance PKA-dependent CREB activation. HDAC inhibitors and PDE-4 antagonists therefore hold therapeutic promise for cognitive deficits associated with RTS. However, it is important to note that these drugs also improved long-term memory in wild-type mice. Importantly, these studies in Cbp+/− mice illustrate the potential power of targeting transcriptional regulatory processes to induce lasting therapeutic changes in the adult brain. In line with this, the work from Meaney and colleagues mentioned above also showed that transcriptional derepression (with the HDAC inhibitor trichostatin A) in adult animals reverses functional consequences (increased stress responsiveness) of early life experiences (maternal care behavior) that are mediated by epigenetic alterations (methylation within the glucocorticoid receptor promoter) (Weaver et al., 2004Weaver I.C. Cervoni N. Champagne F.A. D'Alessio A.C. Sharma S. Seckl J.R. Dymov S. Szyf M. Meaney M.J. Nat. Neurosci. 2004; 7: 847-854Crossref PubMed Scopus (4591) Google Scholar). Tuberous sclerosis complex (TSC) is a single-gene disorder associated with intellectual disability and autism and involves signaling changes that affect translational control; TSC is caused by heterozygous mutations in either the TSC1 or the TSC2 gene (Consortium, 1993Consortium E.C.T.S. 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Developmental brain abnormalities (cortical tubers) and early-onset seizures (infantile spasms) have long been proposed to cause the cognitive disability associated with TSC (O'Callaghan et al., 2004O'Callaghan F.J. Harris T. Joinson C. Bolton P. Noakes M. Presdee D. Renowden S. Shiell A. Martyn C.N. Osborne J.P. Arch. Dis. Child. 2004; 89: 530-533Crossref PubMed Scopus (178) Google Scholar, Raznahan et al., 2007Raznahan A. Higgins N.P. Griffiths P.D. Humphrey A. Yates J.R. Bolton P.F. Psychol. Med. 2007; 37: 1293-1304Crossref PubMed Scopus (36) Google Scholar). Tubers and infantile spasms, however, only partially account for the variability in IQ in TSC subjects (O'Callaghan et al., 2004O'Callaghan F.J. Harris T. Joinson C. Bolton P. Noakes M. Presdee D. Renowden S. Shiell A. Martyn C.N. Osborne J.P. Arch. Dis. Child. 2004; 89: 530-533Crossref PubMed Scopus (178) Google Scholar). Recent work with mouse models of TSC showed that cognitive deficits can emerge in the absence of tubers and spontaneous seizures (Ehninger et al., 2008Ehninger D. Han S. Shilyansky C. Zhou Y. Li W. Kwiatkowski D.J. Ramesh V. Silva A.J. Nat. Med. 2008; 14: 843-848Crossref PubMed Scopus (667) Google Scholar, Goorden et al., 2007Goorden S.M. van Woerden G.M. van der Weerd L. Cheadle J.P. Elgersma Y. Ann. Neurol. 2007; 62: 648-655Crossref PubMed Scopus (205) Google Scholar). Studies with a Tsc2+/− mouse model of tuberous sclerosis demonstrated that TSC-related increases in mTOR signaling lead to an abnormally low threshold for the late phase of LTP: conditions that induced only the unstable early phase of LTP in controls induced instead an abnormally stable potentiation in the mutants (Ehninger et al., 2008Ehninger D. Han S. Shilyansky C. Zhou Y. Li W. Kwiatkowski D.J. Ramesh V. Silva A.J. Nat. Med. 2008; 14: 843-848Crossref PubMed Scopus (667) Google Scholar). Supposedly, this abnormal stabilization of LTP results in the inappropriate consolidation of error-prone information that interferes with normal learning and memory processes in TSC. Strikingly, suppressing mTOR signaling with