Playing on Without AKT1: Subtle Cortical Deficits Suggest Vulnerabilities
21 November 2006. The enzyme AKT1 has been implicated in both schizophrenia and bipolar disorder. A new study in the November 7 issue of PNAS finds that a mouse lacking the gene for AKT1 shows subtle alterations of neuronal morphology in prefrontal cortex, as well as deficits in working memory. Joseph Gogos and Maria Karayiorgou of Columbia University in New York City also report that the absence of AKT1 primarily impacts molecular cascades involved in synaptic function, neuronal development, myelination, and actin polymerization in this cortical region.
Gogos and Karayiorgou first identified AKT1 as a candidate susceptibility gene for schizophrenia in 2004 (see SRF related news story), and it has been linked to bipolar disorder as well (Toyota et al., 2003). The association of the gene with schizophrenia has been supported in some, but not all genetic studies. Most recently, Bajestan and colleagues (2006) found a haplotype of the gene that increased risk for the disorder in an Iranian population.
Notably, AKT1 is a downstream target of dopamine D2 receptors, the main target of antipsychotic drugs. In their original paper, the Gogos and Karayiorgou groups focused on the possibility that altered AKT1 signaling via glycogen synthase kinase (GSK)3β might be involved in the either the pathophysiology of schizophrenia or in the action of antipsychotic drugs. Two subsequent studies have either supported (Zhao et al., 2006) or failed to support (Ide et al., 2006) the implication of altered AKT1/GSK3β signaling in schizophrenia. However, AKT1 is not a one-trick pony—it activates a number of other molecules.
How well does prefrontal cortex get along without AKT1?
In their current update on the AKT1-deficient mouse, first author Wen-Sung Lai and colleagues focus their attention on the prefrontal cortex (PFC), a region critical for working memory and believed by many to be especially vulnerable in schizophrenia. The researchers first report on their efforts to make sense of the myriad changes in gene transcription in prefrontal cortex resulting from AKT1 gene knockout in C57BL/6J mice. They sorted the up- or downregulated mRNA transcripts into functionally related groups, which converged on pathways involved in maintenance of the actin cytoskeleton, as well as more general categories such as neuronal development, synaptic transmission, and myelination. “In all, the combined pattern of concerted alterations in the expression of PFC-expressed genes unveiled by gene-class testing implies that AKT1-deficiency in vivo causes deficits in neuronal development and the establishment of local neuronal architecture and connectivity in PFC,” the authors write.
Lai and colleagues also report evidence of prefrontal cortical abnormalities on histological and behavioral analyses. Using a marker that preferentially labels layer V pyramidal neurons, the major output neurons of the neocortex, the researchers were able to quantify dendritic morphology in these cells. They report that in AKT1-null mice these neurons have a curious shift in morphology—the apical dendritic trees that extend up into more superficial layers are less complex, or “bushy,” than in wild-type mice, whereas the basal dendrites of lower cortical layers are more complex. There was no alteration in the density of dendritic spines in the AKT1 -/- mice.
Probing working memory
The researchers sought to reinforce their hypothesis of prefrontal cortical dysfunction in the AKT1 mice by testing for working memory deficits. After finding that the mutant mice exhibited normal working memory in T-maze experiments, Lai and colleagues tried to bring out more subtle deficits by perturbing different neurotransmitter systems. They found that a selective dopamine D2 receptor agonist caused AKT -/- mice to perform more poorly than wild-type mice in the working memory tasks, whereas activation of D1 receptors produced equivalent perturbations of working memory in both knockout and wild-type mice.
“The observation that the dopamine effect was specific for activation of [the] D2 class of receptors, in agreement with the observation that stimulation of D2 but not D1 class receptors results in a cAMP-independent dephosphorylation and inactivation of AKT, underscores the accuracy and validity of our analysis and indicates that AKT1 deficiency makes working memory performance more vulnerable to the effects of DRD2 but not DRD1 activation,” the authors write. They note that previous research has identified AKT1 as a downstream target of D2 activation and that antipsychotic drugs can affect AKT1 signaling.
Using agents that target other neurotransmitter systems, the researchers were also able to show that AKT1 -/- mice are more sensitive to perturbations in noradrenergic and cholinergic neurotransmission than wild-type mice.
Lai and colleagues acknowledge the huge challenge of tying perturbations in a knockout mouse model to the pathophysiology of schizophrenia, particularly if it is one gene among many susceptibility genes. “In all, the utility of the AKT1 mouse model (and any gene-based model) will critically depend on the experimental level of analysis, and can be enhanced in future experiments by combined modeling of more than one genetic risk factor, which can be achieved by crossing more than one engineered mouse strain or by combined modeling of genetic deficits and environmental influences,” the authors write.—Hakon Heimer.
Lai WS, Xu B, Westphal KG, Paterlini M, Olivier B, Pavlidis P, Karayiorgou M, Gogos JA. Akt1 deficiency affects neuronal morphology and predisposes to abnormalities in prefrontal cortex functioning. Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16906-11. Epub 2006 Oct 31. Abstract. Abstract
Comments on News and Primary Papers
Comment by: Takeo Yoshikawa
, Akihiko Takashima
Submitted 30 November 2006
Posted 30 November 2006
I recommend the Primary Papers
In this study, Karayiorgou and Gogos’s group have conducted a meticulous anatomical analysis of pyramidal cell dendritic structures in the prefrontal layer V cortex, as well as genome-wide expression and pharmaco-behavioral analyses, focusing on prefrontal functions in Akt1-deficient mice. The study examines the reduced (or altered) AKT1-GSK3β signalling theory of schizophrenia, proposed by this (Emamian et al., 2004) and other groups.
AKT1 as a genetic susceptibility gene for schizophrenia shows promise in the Caucasian population but this is not reflected in Asian populations as evidenced by our results (Ide et al., 2006). In addition, even in Caucasians, true causal variants have not been identified. Because of this, schizophrenia researchers are interested in observing disease-relevant phenotypes in Akt1-deficient mice. In this study, they have detected morphological and functional alterations of frontal cortex-related traits in mutant mice using state-of-the-art techniques.
To further strengthen AKT1 as a candidate disease gene in schizophrenia, several issues need to be addressed in the near future. For instance, if a reduction of AKT1 signalling occurs in the brain, tau should be hyper-phosphorylated by activated GSK3β, which in turn will lead to the formation of neurofibrillary tangles (NFTs) as seen in Alzheimer’s disease. Therefore, it would be interesting to determine whether Akt1-deficient mice show a similar pattern of tau phosphorylation. Accumulating evidence suggests that hyper-phosphorylated tau may affect a variety of neuronal functions. Our recent biochemical analyses failed to reveal any significant reduction of AKT-mediated signalling in the prefrontal cortex of schizophrenic brains or the expected inverse correlation between phosphorylation levels of AKT and tau (Ide et al., 2006). This highlights the difficulty of examining protein phosphorylation status using postmortem brains, where results are often confounded by multiple, uncontrollable factors.
Another important but poorly understood point is the functional relationship among subspecies of the AKT family (at least AKT1, AKT2 and AKT3) and GSK3 (GSK3α and GSK3β) (for example see Sale et al., 2005). We look forward to continuing multidisciplinary studies aimed at unravelling the role of the AKT cascade, including the clarification of downstream pathways (Datta et al., 1999; (O’Mahony et al., 2006) in schizophrenia pathology.
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Related News: News Brief: Schizophrenia-linked AKT1 Variant Affects Brain ParametersComment by: Takeo Yoshikawa
, Akihiko Takashima
Submitted 17 June 2008
Posted 17 June 2008
Some researchers in the field of psychiatric genetics have become somewhat pessimistic about the ability to detect robust genotype-phenotype correlations using the diagnostic criteria defined by DSM-IV. If we analyze tens of thousands of samples, the ensuing results may be statistically robust, but still the effect of common variant(s) of each gene will be modest. Recently, Tan et al. (2008) reported that the AKT1 gene SNP rs1130233 and its encompassing haplotypes are significantly associated with IQ/processing speed, activities that may reflect frontal cortex function. They also showed that performance in their psychological test battery is influenced not only by AKT1 genetic variants but also the well-known COMT gene non-synonymous polymorphism (SNP rs4680, Val158Met). By undertaking fMRI analysis, they intertwined the IQ/processing speed-frontal cortex-AKT1 signal-DA system, i.e., the. integration of multidimensional disciplines. In citing references (Meyer-Lindenberg and Weinberger, 2006; Weinberger et al., 2001), they state that “there is a growing body of data showing that genes weakly associated with complex constellations of behavioral symptoms are much more strongly associated with in vivo brain measures.” Indeed, they have succeeded in explaining a possible role for AKT1 in brain execution capability, but have not provided convincing evidence for genetic associations between AKT1 and schizophrenia.
Their current results are elegantly derived from “a complex set of experiments addressing association of multiple variants in a gene with many phenotypic measures.” However, from a genetic perspective, we may still ask the following questions, irrelevant of the current study:
1. What is the genetic component (or heritability) of each psychological and imaging trait? Can variations in some of the psychological/cognitive/intellectual performances be fully captured by a single gene in an experimental set that examines, at the most, a hundred samples? We have learned the hard way from genetic association studies done in the 1990s, which examined a small number of samples, that we simply cannot trust those results. With regard to this point, the heritability calculations of so-called “endophenotypes” as reported by Greenwood et al. (2007) can give helpful information [also see Watanabe et al., 2007, supplementary Table S2]. There is the possibility that the genetic architecture of neurocognitive functions and imaging measures may not be simpler than the current disease category (entity).
2. Given the rapid advances in genotyping technology, we may be able to generate genome-wide genetic test results for every neuropsychiatric trait in the near future.
3. Because of the functional significance of AKT1 and the divergence in the signaling cascade downstream of AKT1, it would be wise to confine analysis to this gene. However, it is frustrating that we still do not know the functionally important SNP(s) of AKT1 in spite of numerous association studies.
4. Nackley et al. (2006) have convincingly demonstrated that the haplotype of the COMT gene constructed by synonymous SNPs has much more functional impact than the Val158Met polymorphism. Therefore, we would like to see the association studies examining this haplotype in future neuropsychiatric studies.
From a biochemical perspective, the following issues would be interesting and future targets for clarification:
1. The authors suggest that the coding synonymous variation of AKT1 affects protein expression, leading to the alteration of frontostriatal function and gray matter volume. The activity of AKT1 is regulated by its phosphorylation status. Therefore, readers would want to know whether the reduction of AKT1 expression levels actually affect the AKT signaling pathway. Behavioral analysis and an MRI study of Akt1 heterozygote knockout mice may provide relevant information.
2. Impairment of the AKT signal is known to result in tau hyperphosphorylation through activation of GSK3 as seen in Alzheimer disease brains. According to this idea, a reduction of AKT levels caused by SNP(s) should elicit hyperphosphorylation of tau and ultimately form neurofibrillary tangles (NFTs). In contrast, there are some reports suggesting the absence of NFTs and neuroinjury in elderly patients with schizophrenia (Arnold et al., 1998; Purohit et al., 1998). It is also reported that GSK3 is reduced in schizophrenia (Beasley et al., 2001). It would be interesting to know whether the genetic variation(s) of AKT1 that induce decreased protein expression affect tau accumulation.
3. Lithium inhibits the arrestin-Akt signal (Beaulieu et al., 2008). If so, it would be interesting to know whether lithium treatment can restore some of the effects of reduced AKT1 expression levels caused by the SNP(s) of interest.
Arnold SE, Trojanowski JQ, Gur RE, Blackwell P, Han LY, Choi C. Absence of neurodegeneration and neural injury in the cerebral cortex in a sample of elderly patients with schizophrenia. Arch Gen Psychiatry 1998 55:225-232. Abstract
Beasley C, Cotter D, Khan N, Pollard C, Sheppard P, Varndell I, Lovestone S, Anderton B, Everall I. Glycogen synthase kinase-3beta immunoreactivity is reduced in the prefrontal cortex in schizophrenia. Neurosci Lett 2001 302:117-120. Abstract
Beaulieu JM, Marion S, Rodriguiz RM, Medvedev IO, Sotnikova TD, Ghisi V, Wetsel WC, Lefkowitz RJ, Gainetdinov RR, Caron MG.. A beta-arrestin 2 signaling complex mediates lithium action on behavior. Cell 2008 132:125-36. Abstract
Greenwood TA, Braff DL, Light GA, Cadenhead KS, Calkins ME, Dobie DJ, Freedman R, Green MF, Gur RE, Gur RC, Mintz J, Nuechterlein KH, Olincy A, Radant AD, Seidman LJ, Siever LJ, Silverman JM, Stone WS, Swerdlow NR, Tsuang DW, Tsuang MT, Turetsky BI, Schork NJ. Initial heritability analyses of endophenotypic measures for schizophrenia: the consortium on the genetics of schizophrenia. Arch Gen Psychiatry 2007 64:1242-1250. Abstract
Meyer-Lindenberg AS, Weinberger DR: Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nat Rev Neurosci 2006 7:818-827. Abstract
Nackley AG, Shabalina SA, Tchivileva IE, Satterfield K, Korchynskyi O, Makarov SS, Maixner W, Diatchenko L: Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science 2006 314:1930-1933. Abstract
Purohit DP, Perl DP, Haroutunian V, Powchik P, Davidson M, Davis KL: Alzheimer disease and related neurodegenerative diseases in elderly patients with schizophrenia: a postmortem neuropathologic study of 100 cases. Arch Gen Psychiatry 1998 55:205-211. Abstract
Tan HY, Nicodemus KK, Chen Q, Li Z, Brooke JK, Honea R, Kolachana BS, Straub RE, Meyer-Lindenberg A, Sei Y, Mattay VS, Callicott JH, Weinberger DR: Genetic variation in AKT1 is linked to dopamine-associated prefrontal cortical structure and function in humans. J Clin Invest 2008 118:2200-2208. Abstract
Watanabe A, Toyota T, Owada Y, Hayashi T, Iwayama Y, Matsumata M, Ishitsuka Y, Nakaya A, Maekawa M, Ohnishi T, Arai R, Sakurai K, Yamada K, Kondo H, Hashimoto K, Osumi N, Yoshikawa T: Fabp7 maps to a quantitative trait locus for a schizophrenia endophenotype. PLoS Biology 2007 5:e297. Abstract
Weinberger DR, Egan MF, Bertolino A, Callicott JH, Mattay VS, Lipska BK, Berman KF, Goldberg TE: Prefrontal neurons and the genetics of schizophrenia. Biol Psychiatry 2001 50:825-844. Abstract
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Related News: DISC1 Players Gird For Adult Neurodevelopment
Comment by: Kevin J. Mitchell
Submitted 8 October 2009
Posted 8 October 2009
The seminal identification of mutations in DISC1 associated with schizophrenia
and other psychiatric disorders raises several obvious questions: what does the
DISC1 protein normally do? What are its biochemical and cellular functions, and
what processes are affected by its mutation? How do defects in these cellular
processes ultimately lead to altered brain function and psychopathology? Which
brain systems are affected and how? Similar questions could be asked for the
growing number of other genes that have been implicated by the identification
of putatively causal mutations, including NRG1, ERBB4, NRXN1, CNTNAP2, and many
copy number variants. Finding the points of biochemical or phenotypic
convergence for these proteins or mutations may be key to understanding how
mutations in so many different genes can lead to a similar clinical phenotype
and to suggesting points of common therapeutic intervention.
The papers by Kim et al. and Enomoto et al. add more detail to the complex
picture of the biochemical interactions of DISC1 and its diverse cellular
functions. The links with Akt and PTEN signaling are especially interesting,
given the previous implication of these proteins in schizophrenia and autism.
Akt, in particular, may provide a link between Nrg1/ErbB4 signaling and DISC1
These studies also reinforce the importance of DISC1 and its interacting
partners in neurodevelopment, specifically in cell migration and axonal
extension. In particular, they highlight the roles of these proteins in
postnatal hippocampal development and adult hippocampal neurogenesis. They
also raise the question of which extracellular signals and receptors regulate
these processes through these signalling pathways. The Nrg1/ErbB4 pathway has
already been implicated, but there are a multitude of other cell migration and
axon guidance cues known to regulate hippocampal development, some of which,
for example, semaphorins, signal through the PTEN pathway.
Whether or how disruptions in these developmental processes contribute to
psychopathology also remains unclear. It seems likely that the effects of
mutations in any of these genes will be highly pleiotropic and have effects in
many brain systems. The reported pathology in schizophrenia is not restricted
to hippocampus but extends to cortex, thalamus, cerebellum, and many other
regions. Similarly, while the cognitive deficits receive a justifiably large
amount of attention, given that they may have the most clinical impact, motor
and sensory deficits are also a stable and consistent part of the syndrome that
must be explained. Pleiotropic effects on prenatal and postnatal development, as
well as on adult processes, may actually be the one common thread characterizing
the genes so far implicated. These new papers represent the first steps in the
kinds of detailed biological studies that will be required to make explanatory
links from mutations, through biochemical and cellular functions, to effects on
neuronal networks and ultimately psychopathology.
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Related News: DISC1 Players Gird For Adult Neurodevelopment
Comment by: Peter Penzes, Michael Cahill
Submitted 8 October 2009
Posted 8 October 2009
DISC1 disruption by chromosomal translocation cosegregates with several neuropsychiatric disorders, including schizophrenia (Blackwood et al., 2001; Millar et al., 2000). Recent attention has focused on the effects of DISC1 on the structure and function of the dentate gyrus, one of the few brain regions that exhibit neurogenesis throughout life. The downregulation of DISC1 has several deleterious effects on the dentate gyrus, including aberrant neuronal migration (Duan et al., 2007). However, the mechanisms through which DISC1 regulates the structure and function of the dentate gyrus remain unknown. The dentate gyrus and its output to the CA3 area, the mossy fiber, show several abnormalities in schizophrenia and other neuropsychiatric diseases (Kobayashi, 2009). Thus, understanding how a gene associated with neuropsychiatric disease, DISC1, mechanistically impacts the dentate gyrus is an important question with much clinical relevance.
The recent papers by Kim et al. and Enomoto et al. characterize an interaction between DISC1 and girdin (also known as KIAA1212), and reveal how girdin, and the interaction between DISC1 and girdin, impact axon development, dendritic development, and the proper positioning of newborn neurons in the dentate gyrus. Girdin normally stimulates the function of AKT (Anai et al., 2005), and Kim et al. show that DISC1 binds to girdin and inhibits its function. Thus, the loss of DISC1 leaves girdin unopposed, resulting in excessive AKT signaling. Indeed, the developmental defects in neurons lacking DISC1 can be rescued by pharmacologically blocking the activation of an AKT downstream target. However, as shown by Enomoto et al., the loss of girdin produces deleterious effects on neuronal morphology, suggesting that a proper balance of girdin function is crucial.
Collectively, these studies thoroughly characterize the interaction between DISC1 and girdin, and shed much light on the consequences of this interaction on neuronal morphology as well as on the positioning of neurons in the dentate gyrus. The role of girdin in the pathology of neuropsychiatric diseases is unknown, and remains an interesting question for the future. Characterizing the molecules that act up- or downstream of DISC1 remains an important area of investigation and could aid the development of pharmacological interventions in the future. It’s intriguing that DISC1 acting through girdin regulates the activity of AKT as AKT1 was previously identified as a schizophrenia risk gene (Emamian et al., 2004). This suggests a convergence of multiple schizophrenia-associated genes in a shared pathway, and thus it will be important to determine if the DISC1-girdin-AKT1 pathway is particularly vulnerable in neuropsychiatric disorders.
Blackwood DH, Fordyce A, Walker MT, St Clair DM, Porteous DJ, Muir WJ. Schizophrenia and affective disorders--cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet . 2001 Aug 1 ; 69(2):428-33. Abstract
Millar JK, Christie S, Semple CA, Porteous DJ. Chromosomal location and genomic structure of the human translin-associated factor X gene (TRAX; TSNAX) revealed by intergenic splicing to DISC1, a gene disrupted by a translocation segregating with schizophrenia. Genomics . 2000 Jul 1 ; 67(1):69-77. Abstract
Duan X, Chang JH, Ge S, Faulkner RL, Kim JY, Kitabatake Y, Liu XB, Yang CH, Jordan JD, Ma DK, Liu CY, Ganesan S, Cheng HJ, Ming GL, Lu B, Song H. Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell . 2007 Sep 21 ; 130(6):1146-58. Abstract
Kobayashi K. Targeting the hippocampal mossy fiber synapse for the treatment of psychiatric disorders. Mol Neurobiol . 2009 Feb 1 ; 39(1):24-36. Abstract
Anai M, Shojima N, Katagiri H, Ogihara T, Sakoda H, Onishi Y, Ono H, Fujishiro M, Fukushima Y, Horike N, Viana A, Kikuchi M, Noguchi N, Takahashi S, Takata K, Oka Y, Uchijima Y, Kurihara H, Asano T. A novel protein kinase B (PKB)/AKT-binding protein enhances PKB kinase activity and regulates DNA synthesis. J Biol Chem . 2005 May 6 ; 280(18):18525-35. Abstract
Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M, Gogos JA. Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat Genet . 2004 Feb 1 ; 36(2):131-7. Abstract
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