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Are Membrane Molecules Unmoored in 22q11DS Mouse?

22 October 2008. In new work on their mouse model of 22q11 deletion syndrome, the research groups of Maria Karayiorgou and Joseph Gogos at Columbia University report that the absence of Zdhhc8, a palmitoyltransferase enzyme, caused dendrites to develop poorly and to have far fewer spines, the knobby dendritic protuberances that form the receiving half of most excitatory synapses. When Zdhhc8 was restored, these abnormalities were prevented in both cultured neurons and in the brains of adult animals, the authors write in a paper published online on 5 October in Nature Neuroscience.

The authors suggest that the chromosomal deletion in their mouse model blocks the post-translational, enzyme-dependent process known as palmitoylation, in which palmitate, a 16-carbon fatty acid, is added to the side chain of an internal cysteine residue in cell membranes. These long hydrophobic chains help to sort and anchor membrane-bound proteins and orient them in relation to the cytosol, a process that is particularly important in the development of synapses. Unlike other protein-sorting mechanisms, palmitoylation is reversible and dynamic, indispensible factors for regulating synaptic plasticity (see El-Husseini and Bredt, 2002; Greaves and Chamberlain, 2007).

Many missing genes
Over the last several years, researchers have amassed a great deal of converging evidence that implicates abnormalities of the chromosome 22q11.2 region in the pathogenesis of schizophrenia. Some of the most suggestive data come from studies of patients with velocardiofacial syndrome, or VCSF, a disorder characterized by cleft palate, cardiac abnormalities, and facial anomalies that arises from a 1.5-3.0 Mbase microdeletion in chromosome 22q11.2. In addition to their physical characteristics, children with VCSF—also known as 22q11 deletion syndrome (22q11DS)—exhibit distinctive emotional and cognitive deficits, and a third of them develop schizophrenia or schizoaffective disorder in adolescence or adulthood, which has stimulated intense interest in 22q11DS among researchers in psychiatric genetics.

About 7 percent of 22q11DS patients carry a 1.5-Mb deletion of a region that contains 27 known genes. Recent studies, including some by the Gogos and Karayiorgou groups, have focused on the functional role of a number of these genes, including catechol-O-methyltransferase (COMT); the myelin-associated gene PIK4CA; the Nogo-66 receptor gene RTN4R; HTF9C, a gene for an RNA binding protein; and proline dehydrogenase (PRODH) (see SRF related news story).

Earlier this year, Gogos’s and Karayiogou’s laboratories published a paper on a mouse model called Df(16)A+/– that was engineered to closely mimic the human 22q11.2 deletion (Stark et al., 2008). A team led by first authors Kimberly Stark and Bin Xu described how the deletion of Dgcr8, a gene that regulates the biogenesis of microRNAs, had widespread effects on gene expression in the hippocampus and prefrontal cortex. That paper also noted behavioral and cognitive deficits, including impairment of prepulse inhibition and fear conditioning and poor performance in spatial-learning tasks, and documented a reduction in dendritic complexity and density of dendritic spines in hippocampal pyramidal neurons (see SRF related news story).

Reversible damage
All but one of the genes affected by 22qDS lie on an orthologous region of mouse chromosome 16 (albeit in a different order), and the deletion in this model covers the same genetic ground as the 1.5 Mbase deletion seen in humans. In the new paper, a group led by first author Jun Mukai concentrated on Zdhhc8, which codes for a putative palmitoyltransferase.

As in the previous work, the researchers again noted a significant reduction in the number of so-called mushroom dendritic spines, a modest but significant reduction in these structures’ length and width, and a reduction in markers associated with pre- and postsynaptic sites.

To tease out the possible role of Zdhhc8 deletion in these effects, the group transfected Df(16)A+/– neurons in culture with a full-length ZDHHC8 expression construct. This manipulation restored the density of dendritic spines and of pre- and postsynaptic markers to wild-type levels, but did not reverse the morphological anomalies in Df(16)A+/– spines, which prompted the authors to propose that dendritic spine size and shape may be governed by Dgcr8 or by other genes deleted in the Df(16)A+/– model.

To further home in on Zdhhc8 deficiency as the possible culprit in the reduction of dendritic spines seen in the Df(16)A+/– mouse, the team examined neurons from homozygous and heterozygous Zdhhc8-knockout mice. They found a dose-dependent reduction in spine density and pre- and postsynaptic markers, and there was no noticeable effect on spine length or width.

In separate experiments, the team documented significant reductions in dendritic complexity in cultured Df(16)A+/– neurons, defined as the number of primary dendrites, the number of their branch points, and their total length. These deficits could also be reversed with ZDHHC8 transfection.

All of these effects seen in vitro on dendritic spine density and complexity, and on pre- and postsynaptic protein markers, were also found in hippocampal neurons from adult Df(16)A+/– and Zdhhc8-knockout mice, though the effects were somewhat smaller than those seen in the experiments in culture, a difference the authors attribute to compensatory developmental mechanisms in the intact animals.

Finally, the researchers showed that PSD95, an important and abundant postsynaptic density protein that has been shown to regulate the number of dendritic spines (Vessey and Karra, 2007), is palmitoylated by Zdhhc8. When this enzymatic process was blocked, normal trafficking of PSD95 to the membrane was disrupted; instead of accumulating in perinuclear regions—a phenomenon that precedes the clustering of the protein in dendrites, where it provides scaffolding for postsynaptic ion channels (El-Husseini et al., 2000)—PSD95 was located diffusely in the cytoplasm.

The authors propose that disrupted ZDHHC8-dependent palmitoylation, combined with aberrant miRNA biogenesis, contributes to the behavior and cognitive phenotypes seen in 22q11DS. They go on to suggest that hemi-deletion of the COMT and PRODH genes found in this chromosomal region, and consequent abnormal dopamine neurotransmission, “could further alter network properties, modify the cognitive phenotypes and possibly predispose a subset of 22q11 microdeletion carriers to psychiatric symptoms.”—Peter Farley.

Reference:
Mukai J, Dhilla A, Drew LJ, Stark KL, Cao L, Macdermott AB, Karayiorgou M, Gogos JA. Palmitoylation-dependent neurodevelopmental deficits in a mouse model of 22q11 microdeletion. Nat Neurosci, 5 October 2008 (Advance online publication). Abstract

Comments on News and Primary Papers
Comment by:  Doron Gothelf
Submitted 27 October 2008
Posted 27 October 2008

The common theory held until recently regarding the genetic underpinning of neuropsychiatric disorders was based on the “common disease-common variant” model. According to that theory, multiple common alleles in the population contribute small-to-moderate additive or multiplicative effects to the predisposition to neuropsychiatric disorders. With the advances in genetic screening technologies this theory is now being challenged. Recent findings indicate that rare copy number variations (CNVs) may account for a substantial fraction of the overall genetic risk for neuropsychiatric disorders including schizophrenia and autism (Consortium, 2008; Stefansson et al., 2008; Mefford et al., 2008). The 22q11.2 microdeletion was the most common CNV identified in patients with schizophrenia in a recent large scale study of patients with schizophrenia (Consortium, 2008). The 22q11.2 microdeletion is also the most common microdeletion occurring in humans and up to one third of individuals with 22q11.2 deletion syndrome (22q11.2DS) develop schizophrenia by adulthood. Thus the syndrome serves as an important model from which to learn the path leading from a well defined genetic defect to brain development and eventually to the evolution of schizophrenia.

It is still uncertain whether the neuropsychiatric phenotype associated with 22q11.2DS is a result of a strong effect of haploinsufficiency of one or a few genes from the microdeletion region as some studies suggested (Gothelf et al., 2005; Paterlini et al., 2005; Raux et al., 2007; Vorstman et al., 2008), or the result of cumulative small effects of haploinsufficiency of multiple genes, each contributing a small effect, as other studies suggested (Maynard et al., 2003; Meechan et al., 2006).

The current very elegant study by Mukai and colleagues suggests that haploinsufficiency of a single gene from the 22q11.2 deleted region, Zdhhc8, is responsible for the microscopic neural hippocampal abnormalities present in a mouse model of the disease. Remarkably, these abnormalities were prevented with the reintroduction of enzymatically active ZDHHC8 protein. The works of Gogos and his colleagues (Paterlini et al., 2005; Stark et al., 2008) are consistently and brilliantly getting us closer to revealing the complex association between genes from the 22q11.2 region and the neuropsychiatric phenotype. If indeed haploinsuffiency of single genes like Zdhhc8, COMT, or Dgcr8 have a strong effect on abnormal brain development and the eruption of schizophrenia, it conveys an enormous potential for developing novel pathophysiologically based treatments for this refractory disease. Such treatments will target the enzymatic deficit conveyed by the genetic mutation.

References:

[No authors listed]. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 2008 Sep 11;455(7210):237-41. Abstract

Stefansson H, Rujescu D, Cichon S, Pietiläinen OP, Ingason A, Steinberg S, Fossdal R, Sigurdsson E, Sigmundsson T, Buizer-Voskamp JE, Hansen T, Jakobsen KD, Muglia P, Francks C, Matthews PM, Gylfason A, Halldorsson BV, Gudbjartsson D, Thorgeirsson TE, Sigurdsson A, Jonasdottir A, Jonasdottir A, Bjornsson A, Mattiasdottir S, Blondal T, Haraldsson M, Magnusdottir BB, Giegling I, Möller HJ, Hartmann A, Shianna KV, Ge D, Need AC, Crombie C, Fraser G, Walker N, Lonnqvist J, Suvisaari J, Tuulio-Henriksson A, Paunio T, Toulopoulou T, Bramon E, Di Forti M, Murray R, Ruggeri M, Vassos E, Tosato S, Walshe M, Li T, Vasilescu C, Mühleisen TW, Wang AG, Ullum H, Djurovic S, Melle I, Olesen J, Kiemeney LA, Franke B, Sabatti C, Freimer NB, Gulcher JR, Thorsteinsdottir U, Kong A, Andreassen OA, Ophoff RA, Georgi A, Rietschel M, Werge T, Petursson H, Goldstein DB, Nöthen MM, Peltonen L, Collier DA, St Clair D, Stefansson K, Kahn RS, Linszen DH, van Os J, Wiersma D, Bruggeman R, Cahn W, de Haan L, Krabbendam L, Myin-Germeys I. Large recurrent microdeletions associated with schizophrenia. Nature. 2008 Sep 11;455(7210):232-6. Abstract

Mefford HC, Sharp AJ, Baker C, Itsara A, Jiang Z, Buysse K, Huang S, Maloney VK, Crolla JA, Baralle D, Collins A, Mercer C, Norga K, de Ravel T, Devriendt K, Bongers EM, de Leeuw N, Reardon W, Gimelli S, Bena F, Hennekam RC, Male A, Gaunt L, Clayton-Smith J, Simonic I, Park SM, Mehta SG, Nik-Zainal S, Woods CG, Firth HV, Parkin G, Fichera M, Reitano S, Lo Giudice M, Li KE, Casuga I, Broomer A, Conrad B, Schwerzmann M, Räber L, Gallati S, Striano P, Coppola A, Tolmie JL, Tobias ES, Lilley C, Armengol L, Spysschaert Y, Verloo P, De Coene A, Goossens L, Mortier G, Speleman F, van Binsbergen E, Nelen MR, Hochstenbach R, Poot M, Gallagher L, Gill M, McClellan J, King MC, Regan R, Skinner C, Stevenson RE, Antonarakis SE, Chen C, Estivill X, Menten B, Gimelli G, Gribble S, Schwartz S, Sutcliffe JS, Walsh T, Knight SJ, Sebat J, Romano C, Schwartz CE, Veltman JA, de Vries BB, Vermeesch JR, Barber JC, Willatt L, Tassabehji M, Eichler EE. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med. 2008 Oct 16;359(16):1685-99. Abstract

Gothelf D, Eliez S, Thompson T, Hinard C, Penniman L, Feinstein C, Kwon H, Jin S, Jo B, Antonarakis SE, Morris MA, Reiss AL. COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. Nat Neurosci. 2005 Nov 1;8(11):1500-2. Abstract

Paterlini M, Zakharenko SS, Lai WS, Qin J, Zhang H, Mukai J, Westphal KG, Olivier B, Sulzer D, Pavlidis P, Siegelbaum SA, Karayiorgou M, Gogos JA. Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice. Nat Neurosci. 2005 Nov 1;8(11):1586-94. Abstract

Raux G, Bumsel E, Hecketsweiler B, van Amelsvoort T, Zinkstok J, Manouvrier-Hanu S, Fantini C, Brévière GM, Di Rosa G, Pustorino G, Vogels A, Swillen A, Legallic S, Bou J, Opolczynski G, Drouin-Garraud V, Lemarchand M, Philip N, Gérard-Desplanches A, Carlier M, Philippe A, Nolen MC, Heron D, Sarda P, Lacombe D, Coizet C, Alembik Y, Layet V, Afenjar A, Hannequin D, Demily C, Petit M, Thibaut F, Frebourg T, Campion D. Involvement of hyperprolinemia in cognitive and psychiatric features of the 22q11 deletion syndrome. Hum Mol Genet. 2007 Jan 1;16(1):83-91. Abstract

Vorstman JA, Chow EW, Ophoff RA, van Engeland H, Beemer FA, Kahn RS, Sinke RJ, Bassett AS. Association of the PIK4CA schizophrenia-susceptibility gene in adults with the 22q11.2 deletion syndrome. Am J Med Genet B Neuropsychiatr Genet. 2008 Jul 21; Abstract

Maynard TM, Haskell GT, Peters AZ, Sikich L, Lieberman JA, LaMantia AS. A comprehensive analysis of 22q11 gene expression in the developing and adult brain. Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14433-8. Abstract

Meechan DW, Maynard TM, Wu Y, Gopalakrishna D, Lieberman JA, LaMantia AS. Gene dosage in the developing and adult brain in a mouse model of 22q11 deletion syndrome. Mol Cell Neurosci. 2006 Dec 1;33(4):412-28. Abstract

Stark KL, Xu B, Bagchi A, Lai WS, Liu H, Hsu R, Wan X, Pavlidis P, Mills AA, Karayiorgou M, Gogos JA. Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat Genet. 2008 Jun 1;40(6):751-60. Abstract

View all comments by Doron Gothelf

Comments on Related News


Related News: Chromosome 22 Link to Schizophrenia Strengthened

Comment by:  Anthony Grace, SRF Advisor (Disclosure)
Submitted 5 November 2005
Posted 5 November 2005

The fact that the PRODH alteration studied in Gogos et al. leads to alterations in glutamate release, and this corresponds to deficits in associative learning and response to psychotomimetics, provides a nice parallel to the human condition. The Reiss paper examines humans with the 22q11.2 deletion, and shows that the COMT low-activity allele of this deletion syndrome correlates with cognitive decline, PFC volume, and development of psychotic symptoms. This is a nice addition to the Weinberger and Bilder papers about how COMT can lead to psychosis vulnerability.

View all comments by Anthony Grace

Related News: Chromosome 22 Link to Schizophrenia Strengthened

Comment by:  Caterina Merendino
Submitted 5 November 2005
Posted 5 November 2005
  I recommend the Primary Papers

Related News: Chromosome 22 Link to Schizophrenia Strengthened

Comment by:  Leboyer Marion
Submitted 6 November 2005
Posted 6 November 2005
  I recommend the Primary Papers

Related News: Chromosome 22 Link to Schizophrenia Strengthened

Comment by:  Anne Bassett
Submitted 7 November 2005
Posted 7 November 2005
  I recommend the Primary Papers

I echo Jeff Lieberman's comment regarding previous reports of a weak association between the Val COMT functional allele and schizophrenia. Notably, the most recent meta-analysis (Munafo et al., 2005) shows no significant association. Even in 22q11.2 deletion syndrome (22qDS), our group (unpublished) and Murphy et al. (1999) have reported that there is no association between COMT genotype and schizophrenia, and Bearden et al. reported that Val-hemizygous patients performed significantly worse than Met-hemizygous patients on executive cognition ( 2004) and childhood behavioral problems (2005). Though important as an initial prospective study, there is a risk in the Gothelf et al. small sample size and multiple testing for type 1 errors. Certainly, there is little evidence, even in 22qDS, for COMT (or PRODH) as “key” risk factors for schizophrenia. There may be some evidence for small effects on cognitive or other measures. Regardless, there is not “extreme deficiency” in COMT activity in the many individuals with Met-hemizygosity in 22qDS, or Met-Met homozygosity in the general population.

Regarding the news item, there are a few widely held misconceptions about 22qDS. Our recent article (Bassett et al., 2005) shows that, accounting for ascertainment bias, the rate of schizophrenia was 23 percent, and congenital heart defects was 26 percent. Of the other 41 common lifetime features of 22qDS (found in 5 percent or more patients), neuromuscular palatal anomalies were common but overt cleft palate was so rare it did not meet inclusion criteria; intellectual disabilities ranged from severe mental retardation (rare) to average intellect (rare) with most patients falling in the borderline range of intellect; and on average, patients had nine of 43 common features. We propose clinical practice guidelines for adults with 22qDS which may be directly applicable to the 1-2 percent of patients with a 22qDS form of schizophrenia.

References:
Bassett AS, Chow EWC, Husted J, Weksberg R, Caluseriu O, Webb GD, Gatzoulis MA. Clinical features of 78 adults with 22q11 Deletion Syndrome. Am J Med Genet A. 2005 Nov 1;138(4):307-13. Abstract

Bearden CE, Jawad AF, Lynch DR, Sokol S, Kanes SJ, McDonald-McGinn DM, Saitta SC, Harris SE, Moss E, Wang PP, Zackai E, Emanuel BS, Simon TJ. Effects of a functional COMT polymorphism on prefrontal cognitive function in patients with 22q11.2 deletion syndrome. Am J Psychiatry . 2004 Sep;161(9):1700-2. Abstract

Bearden CE, Jawad AF, Lynch DR, Monterossso JR, Sokol S, McDonald-McGinn DM, Saitta SC, Harris SE, Moss E, Wang PP, Zackai E, Emanuel BS, Simon TJ. Effects of COMT genotype on behavioral symptomatology in the 22q11.2 Deletion Syndrome. Neuropsychol Dev Cogn C Child Neuropsychol. 2005 Feb;11(1):109-17. Abstract

Munafo MR, Bowes L, Clark TG, Flint J. Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case-control studies. Mol Psychiatry. 2005 Aug;10(8):765-70. Abstract

Murphy KC, Jones LA, Owen MJ. High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry. 1999 Oct 1;56(10):940-5. Abstract

View all comments by Anne Bassett

Related News: 22q11 and Schizophrenia: New Role for microRNAs and More

Comment by:  Linda Brzustowicz
Submitted 21 May 2008
Posted 21 May 2008

While some have expressed frustration over the lack of clear reproducibility of linkage and association findings in schizophrenia, the importance of the chromosome 22q11 deletion syndrome (22q11DS) as a real and significant genetic risk factor for schizophrenia has often been overlooked. While the deletion syndrome is present in a minority of individuals with schizophrenia (estimates of approximately 1 percent), presence of the deletion increases risk of developing schizophrenia some 30-fold, making this one of the clearest known genetic risk factors for a psychiatric illness. As multiple genes are deleted in 22q11DS, it can be a challenge to determine which gene or genes are involved in specific phenotypic elements of this syndrome.

The May 11, 2008, paper by Stark et al. highlights the utility of engineered animals for dissecting the individual effects of multiple genes within a deletion region and provides an important clue into the mechanism likely responsible for at least some of the behavioral aspects of the phenotype. While some may argue about the full validity of animal models of complex human behavior disorders, these systems do have an advantage in manipulability that cannot be achieved in work with human subjects. A key feature of this paper is the comparison of the phenotype of mice engineered to contain a 1.3 Mb deletion of 27 genes with mice engineered to contain a disruption of only one gene in the region, DGCR8. The ability to place both of these alterations on the same genetic background and then do head-to-head comparisons on a number of behavioral, neuropathological, and gene expression assays allows a clear assessment of which components of the mouse phenotype may be attributed specifically to DGCR8 haploinsufficiency. Perhaps not surprisingly, DGCR8 seems to play a role in some, but not all, of the behavioral and neuropathological changes seen in the animals with the 1.3 Mb deletion. The fact that the DGCR8 disruption was able to recapitulate certain elements of the full deletion in the mice does raise its profile as an important candidate gene for some of the neurocognitive elements of 22q11DS, and makes it a potential candidate gene for contributing to schizophrenia risk in individuals without 22q11DS.

Also of great interest is the known function of DGCR8. While the gene name simply stands for DiGeorge syndrome Critical Region gene 8, it is now known that this gene plays an important role in the biogenesis of microRNAs, small non-coding RNAs that regulate gene expression by targeting mRNAs for translational repression or degradation. As miRNAs have been predicted to regulate over 90 percent of genes in the human genome (Miranda et al., 2006), a disruption in a key miRNA processing step could have profound regulatory impacts. Indeed, as reported in the Stark et al. paper and elsewhere (Wang et al., 2007), homozygous deletion of DGCR8 function is lethal in mice. What perhaps seems to be the most surprising result is that haploinsufficiency of DGCR8 function does not induce a more profound phenotype, given the large number of genes that would be expected to be affected if miRNA processing were globally impaired. The Stark et al. paper determined that while the pre-processed form of miRNAs may be elevated in haploinsufficient mice, perhaps only 10-20 percent of all mature miRNAs show altered levels, suggesting that some type of compensatory mechanism may be involved in regulating the final levels of the other miRNAs. Still, the 20-70 percent decrease in the abundance of these altered miRNAs could have a profound effect on multiple cellular processes, given the regulatory nature of miRNAs. In the context of the recent evidence for altered levels of some miRNA in postmortem samples from individuals with schizophrenia (Perkins et al., 2007), the Stark et al. paper adds further support for studying miRNAs as potential candidate genes in all individuals with schizophrenia, not just those with 22q11DS. This paper should serve as an important reminder of how careful analysis of a biological subtype of a disorder can reveal important insights that will be relevant to a much broader set of affected individuals.

References:

1. Stark KL, Xu B, Bagchi A, Lai WS, Liu H, Hsu R, Wan X, Pavlidis P, Mills AA, Karayiorgou M, Gogos JA. Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat Genet. 2008 May 11; Abstract

2. Miranda KC, Huynh T, Tay Y, Ang YS, Tam WL, Thomson AM, Lim B, Rigoutsos I. A pattern-based method for the identification of MicroRNA binding sites and their corresponding heteroduplexes. Cell. 2006 Sep 22;126(6):1203-17. Abstract

3. Wang Y, Medvid R, Melton C, Jaenisch R, Blelloch R. DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal. Nat Genet. 2007 Mar 1;39(3):380-5. Abstract

4. Perkins DO, Jeffries CD, Jarskog LF, Thomson JM, Woods K, Newman MA, Parker JS, Jin J, Hammond SM. microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder. Genome Biol. 2007 Jan 1;8(2):R27. Abstract

View all comments by Linda Brzustowicz

Related News: Working Memory, Cortical Circuitry Disrupted in 22q11DS Mouse Model

Comment by:  Anthony-Samuel LaMantia
Submitted 5 April 2010
Posted 5 April 2010

In a recent report, Sigurdsson et al. provide data that synchrony between hippocampal and cortical activity is subtly altered during a specific spatial motor memory task in a mouse model of the 22q11 Deletion syndrome (also known as DiGeorge syndrome). There have been several studies of other mouse models of 22q11 Deletion syndrome, the first of which were published in the late 1990s and early 2000s (Lindsey et al., 1999; Merscher et al., 2001). All of the data indicate that the development and function of the cerebral cortex is compromised by diminished dosage of the approximately 30 genes whose deletion is obligate in the disease. The reason for the intense interest in 22q11 Deletion syndrome is the high (but not invariant) incidence of schizophrenia in patients with this genetic disorder.

The likely disruption of hippocampal/cortical circuitry, based on subtly altered synchrony (but not, apparently, synaptic connectivity) makes sense if one assumes that diminished dosage of 22q11 genes compromises local circuit organization without wholesale changes in basic mechanisms of synaptic communication. Such results can be compared—cautiously—to hypotheses of regional/circuit malfunction in schizophrenic patients. The synchrony argument is intriguing, especially given the currency of models of cognition that invoke oscillatory behavior of forebrain circuits to explain coherence between diverse, related representations that are thought necessary for cognition and complex behaviors. Nevertheless, it is not clear that current experimental methods in humans can identify the subtle task-dependent dysregulation of synchrony that goes awry in the mouse. Thus, the report by Sigurdsson et al., while intriguing, provides a novel starting point for further investigation. Several questions arise in the mouse model: is cortical or hippocampal circuitry compromised in some way that goes beyond detectable changes in synaptic transmission? If so, how? Is some additional neuronal population that receives information from or provides input to both regions compromised by 22q11 deletion? Finally, how do such abnormalities arise? Are they the result of altered development, or disruptions in mature neuronal function?

While these observations raise exciting possibilities for further research in the relationship between 22q11 Deletion syndrome and schizophrenia pathology, some issues should be considered when comparing the mouse work and human disease. It remains difficult to confirm whether the sort of spatial memory tasks used by Sigurdsson et al. are really examples of mouse “executive function,” “working memory,” or the sorts of cognitive domains thought to be selectively compromised in schizophrenic patients. Moreover, it is generally agreed by comparative neuro-anatomists that the mouse does not have "prefrontal cortex" that is comparable to that seen in non-human and human primates—especially the dorsolateral prefrontal cortex. In humans, the performance of working memory tasks relies upon the integrity of this region, and its connections with a number of other cortical and subcortical areas. These circuits remain the focus of investigation in human schizophrenia pathology. Thus, while dysregulation of hippocampal activity and motor association cortical activity in the frontal aspect of the mouse brain (which is not actually prefrontal cortex) is likely occurring in 22q11 Deletion syndrome model mice, additional work must be done to determine how this relates to human behavioral disruptions in schizophrenia.

References:

Lindsay EA, Botta A, Jurecic V, Carattini-Rivera S, Cheah YC, Rosenblatt HM, Bradley A, Baldini A. Congenital heart disease in mice deficient for the DiGeorge syndrome region. Nature . 1999 Sep 23 ; 401(6751):379-83. Abstract

Merscher S, Funke B, Epstein JA, Heyer J, Puech A, Lu MM, Xavier RJ, Demay MB, Russell RG, Factor S, Tokooya K, Jore BS, Lopez M, Pandita RK, Lia M, Carrion D, Xu H, Schorle H, Kobler JB, Scambler P, Wynshaw-Boris A, Skoultchi AI, Morrow BE, Kucherlapati R. TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell . 2001 Feb 23 ; 104(4):619-29. Abstract

View all comments by Anthony-Samuel LaMantia

Related News: Working Memory, Cortical Circuitry Disrupted in 22q11DS Mouse Model

Comment by:  Wendy Kates
Submitted 7 April 2010
Posted 8 April 2010

The links between genetic variants, neural circuitry, and cognitive dysfunction in schizophrenia are not well understood, due in part to the diagnostic and etiological heterogeneity of schizophrenia, which creates enormous challenges to understanding its pathophysiology. Several research groups are responding to this challenge by investigating the etiologically homogeneous microdeletion disorder, 22q11.2 deletion syndrome (22q11.2 DS), which poses the highest known genetic risk for schizophrenia, second only to having two parents with the disorder. Accordingly, 22q11.2 DS is a compelling model for understanding the pathophysiology of cognitive dysfunction in schizophrenia. Gogos, Karayiorgou, Sigurdsson, and colleagues are investigating this issue with a mouse model of 22q11.2 DS, and their latest, high-impact study of functional connectivity in the context of a working memory paradigm has brought us palpably closer to understanding these elusive links. They elegantly demonstrate that the 22q11.2 microdeletion disrupts prefrontal-hippocampal synchrony, which, in turn, likely contributes to impairments in working memory performance.

Although the specific genes within the microdeletion that are linked to neurocognitive deficits still need to be identified, this study begins to disentangle the complex associations among genetic variants, neural connectivity, and cognition in 22q11.2 DS. The elegance of a mouse model is that it can utilize methods that provide exquisite temporal and spatial resolution that is very difficult to obtain in human studies. Thus, this study identifies, at the neuronal level, disruptions in timing and connectivity that may underlie the white matter deficits that have been observed in neuroimaging studies (Barnea-Goraly et al., 2003; Kates et al., 2001; Simon et al., 2005) of patients with this genetic syndrome, and that putatively account for some of the syndrome’s prominent neurocognitive deficits. These findings provide support for future, more focused studies of neural connectivity, using EEG and diffusion tensor imaging, in patients with this mutation as well as the larger population of patients with schizophrenia.

References:

Barnea-Goraly N, Menon V, Krasnow B, Ko A, Reiss A, Eliez S. (2003) Investigation of white matter structure in velocardiofacial syndrome: a diffusion tensor imaging study. Am J Psychiatry, 160 (10): 1863-9. Abstract

Kates WR, Burnette CP, Jabs EW, Rutberg J, Murphy AM, Grados M, Geraghty M, Kaufmann WE, Pearlson GD. (2001) Regional cortical white matter reductions in velocardiofacial syndrome: a volumetric MRI analysis. Biol Psychiatry, 49 (8): 677-84. Abstract

Simon TJ, Ding L, Bish JP, McDonald-McGinn DM, Zackai EH, Gee J. (2005) Volumetric, connective, and morphologic changes in the brains of children with chromosome 22q11.2 deletion syndrome: an integrative study.Neuroimage. 25 (1): 169-80. Abstract

View all comments by Wendy Kates