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Mapping of Hippocampal Gene Clusters Regulated by the Amygdala

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Mapping of Hippocampal Gene Clusters Regulated by the Amygdala Molecular Psychiatry (2006) 11, 158–171 & 2006 Nature Publishing Group All rights reserved 1359-4184/06 $30.00 www.nature.com/mp ORIGINAL ARTICLE Mapping of hippocampal gene clusters regulated by the amygdala to nonlinkage sites for schizophrenia RE Burke1, J Walsh1, D Matzilevich1,3 and FM Benes1,2,3 1Program in Structural and Molecular Neuroscience, McLean Hospital, Belmont, MA, USA; 2Program in Neuroscience, Harvard Medical School, Boston, MA, USA and 3Department of Psychiatry, Harvard Medical School, Boston, MA, USA A recent study using a ‘partial’ rodent model of schizophrenia has employed amygdalar activation to induce reported changes in the expression of hippocampal genes associated with metabolic and signaling pathways in response to amygdalar activation. The amygdalo– hippocampal pathway plays a central role in the regulation of the stress response and emotional learning. In the current study, we have performed a chromosome mapping analysis to determine whether genes showing changes in response to environmental stress may form clusters and, if so, whether they might show a topographical association with linkage sites for schizophrenia. When the hippocampal genes showing changes in expression were topographically mapped on specific rat chromosomes, significant clustering was observed on chromosomes 1, 4 and 8, although chromosome 1 showed the largest amount of clustering. When these same rodent genes were mapped to human chromosomes, most of the genes found on chromosome 1 in rat mapped to chromosome 11 in human. The vast majority of the genes showing changes in regulation were excluded from known linkage sites for schizophrenia. Based on these findings, we postulate that environmental factors may contribute to the endophenotype for schizophrenia through the activation and/or deactivation of specific genetic clusters, ones that do not appear to be directly associated with susceptibility genes for this disorder. Molecular Psychiatry (2006) 11, 158–171. doi:10.1038/sj.mp.4001769; published online 22 November 2005 Keywords: rodent model; picrotoxin; chromosomes 1; chromosome 11; environmental regula- tion; homology Introduction hippocampal pathway plays a central role in mediat- ing environmental stress responses and also contri- After many years of intensive family studies and butes to the encoding of context-dependent explicit linkage analysis,1 it is now generally believed that memory by the hippocampus.7 Evidence for GABAer- schizophrenia is best explained by a two factor model gic dysfunction has been reported in both the in which both genetic and environmental factors are amygdala8 and hippocampus9–15). Based on these needed to express the clinical phenotype.2,3 To date, studies, particularly those showing changes in the susceptibility genes for this disorder have eluded regulation of the GABA receptor, and the preferential identification and this has made it difficult to under- A distribution of abnormalities in sectors CA3 and CA2 stand how their expression may be influenced by (for reviews, see, Benes and Berretta6), the amygdalo– environmental factors. Indeed, there may be sets of hippocampal pathway is believed to play a pivotal genes independently regulated by environmental role in the pathophysiology of psychotic disor- influences that exist in parallel with susceptibility ders.16,17 Using the ‘partial’ model in which picro- genes and possibly influence their expression pat- toxin, a noncompetitive antagonist of the GABA-A terns.4,5 receptor, is infused into the basolateral nucleus of the To explore this hypothesis, we have used a ‘partial’ amygdala,18,19 we reported complex changes in the rodent model6 to investigate how hippocampal genes genetic regulation of hippocampal cells, particularly showing changes in regulation in response to amyg- in the monoamine and peptide G-protein coupled dalar activation are topographically mapped in rela- pathways in response to amygdalar activation.20 tion to the rat and human genome. The amygdalo– These data support a model in which amygdalar activation of the hippocampus results in regulatory Correspondence: Dr FM Benes, Program in Structural and changes of long-term potential (LTP) and/or apopto- Molecular Neuroscience, McLean Hospital, 115 Mill Street, sis.21,22 Accordingly, these findings have raised Belmont, MA 02478, USA. E-mail: [email protected] important questions as to whether the various genes Received 9 June 2004; revised 28 June 2005; accepted 4 October showing changes in expression in response 2005; published online 22 November 2005 to amygdalar activation of the hippocampus are Mapping hippocampal gene clusters RE Burke et al 159 randomly distributed throughout the genome or from the Online Mendelian Inheritance in Man whether perhaps they may be clustered together on (OMIM) database32 and compared to the locations of particular chromosomes, perhaps in arrangements the human homologs of our rat genes-of-interest to that would facilitate epigenetic regulation.23 It is also detect the amount of overlap (Figure 2). The OMIM important to know whether there is a positional database is useful as a curated repository of informa- relationship between genes associated with the heri- tion about genetic disease, including current informa- tability of schizophrenia24 versus those more likely to tion about linkage areas with significant logarithm-of- be associated with the response to environmental odds (LOD) scores. MIM #181500 was used for the stress. Such information can potentially help define sites of genetic linkage as it provides an overview of whether the interaction of inherited genes and the published literature. Published support for these environmental factors in schizophrenia might occur linkage sites can be found in each MIM listed in the at the genomic level or perhaps at the level of Works Cited (181500, 603342, 181510, 600511, functional neural circuits. 603013, 603176, 605419, 603206, 600850, 192430, To begin to address these issues, we describe below 188400 and 604906, more than 200 linkage studies the results of a topographical analysis of the distribu- in all). tion of hippocampal genes that show regulatory In order to determine whether or not the 78 genes- changes following acute amygdalar activation. To of-interest were randomly distributed across the our knowledge, this is the first study to evaluate the rat genome (in other words, if the distribution of potential association between environmentally regu- the genes-of-interest was independent of the chromo- lated genes and established linkage sites for schizo- some number or if a disproportionate number of phrenia. genes-of-interest localized to one or more chromo- somes), an R  C (21 row  2 column) G-test 33 Materials and methods of independence was used. An a priori assumption of a random distribution of the genes-of-interest The ‘partial’ model study was conducted as des- seems appropriate given the relatively large number cribed.20 Briefly, a subepileptic dose of picrotoxin of genes from each chromosome on the Affymetrix (PICRO; 50 ng/0.8 ml; RBI, Natick, MA, USA) or RG-U34A chip and the relatively small number vehicle (VEH) was continuously infused over a period of genes-of-interest. The human genome contains of 96 h via a cannula stereotaxically placed in the nonrandom clusters of both genes with high expres- basolateral nucleus of the amygdala of 20 Sprague– sion levels expressed in many different tissues Dawley rats. The animals were killed 96 h later (ridges) and genes with low expression levels and and the hippocampus was removed, flash frozen, more tissue-specific expression (antiridges).34 How- and its RNA was processed for interrogation ever, it seems most appropriate to determine if there is with Affymetrix RG-U34A rat genome arrays. Statis- any clustering first by assuming a random distribu- tical analyses were performed on the arrays using tion, then assessing whether the clustering fits into the Affymetrix MicroArray Suite (Affymetrix, Santa either of the two preceding categories. The G-test is an Clara, CA, USA), dChip (www.dchip.org),25,26 and appropriate statistical test for determining whether or GenMAPP (www.genmapp.org)27 to identify only not an independent relationship exists between two biologically relevant genes-of-interest that showed categories or attributes.33 In this case, the number of significantly altered expression levels in the PICRO genes changed and the chromosome number (e.g. rats when compared to VEH rats (determined chromosome 12) were the two categories. The absence by t-test (Pp0.25))20). The data used for the current of an association between genes-of-interest and a analysis can be accessed through the following particular chromosome (12, for example) would URL: www.mclean.harvard.edu/research/mrc/bene- suggest that the changes in gene expression induced sville.php. by the ‘partial’ model are randomly distributed across The NetAffx database (www.netaffx.com)28 was the rat genome when considered on a chromosome- used to obtain the genomic locations of the genes-of- by-chromosome basis. Information concerning how interest in this study. NetAffx utilizes the University many genes from each rat chromosome are on the RG- of California at Santa Cruz (UCSC) Genome Bioinfor- U34A chip was derived from the UCSC Genome matics database for this information.29 Of the 85 Bioinformatics29 and Affymetrix NetAffx28 web pages. genes-of-interest, 78 had documented > 99% se- The expression levels and breadth of expression quence homology with a known region
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