The neurobiology of cognitive dysfunction in schizophrenia: Insights from gene expression profiling

S. 16. Molecular strategies for understanding neuropsychiatric disorders Our studies provide evidence that cannabinoid-induced cognitive deficits may be a useful model for the neurocognitive dysfimction, particularly attention deficits, in schizophrenia. Further studies are required to determine the construct validity of the performance impairments reported here, and on-going studies are examining the specific pharmacology that underlies the attention deficits, particularly those resulting from chronic cannabinoid administration. These studies were funded in part by PHS grants MH57483 (RHR), DA11717 (JRT) and by NARSAD (RHR,JRT).

References [1] Green, M.F. and K.H. Nuechterlein, Should schizophrenia be treated as a neurocognitivedisorder? Schizophr Bull, 1999. 25(2): p. 309-19. [2] Cannon, T.D., et al., Quantitative neural indicators of liability to schizophrenia: implications for molecular genetic studies. Am J Med Genet, 2001. 105(1): p. 16-9. [3] Pope, H.G., Jr., et al., Neuropsychologicalperformance in long-term cannabis users. Arch Gen Psychiatry, 2001. 58(10): p. 909-15. [4] Hall, W. and N. Solowij, Adverse effects of cannabis. Lancet, 1998. 352(9140): p. 1611~5.

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value of transgenic and gene targeted models for experimental therapeutics of Alzheimer's disease

D.L. Price 1'2'3'4, H.B. Cai 1'4, A. Savonenko1'4, D.R. Borchelt 1'4, P.C. Wong 1'4. Departments of 1Pathology, ZNeurology, 3Neuroscience, and 4the Division of Neuropathology, The Johns Hopkins University School of Medicine, Baltimore, MD, US.A. Alzheimer's disease (AD) is associated with characteristic clinical signs, specific risk factors (genes), dysfunction/death of specific subsets of neurons, and disease-defining pathological/biochemical abnormalities. Transgenic and gene targeting strategies have been very useful for studies designed to understand disease mechanisms, identifying therapeutic targets, and designing/testing novel treatments. To create mice with A[3 deposits in brain, we made transgenic mice expressing the autosomal dominant familial AD (FAD) mutant genes encoding the amyloid precursor protein (APP) or presenilins (PSI) which influence the levels or length of AI3, a 4kD toxic peptide, deposited in the brains of individuals with AD. A[3 is generated by cleavages of APP by fS-secretase 1 (BACE 1) and by y-secretase (which is influenced by presence of PS1/2). Transgenic mice overexpressing mutant APP or APP PS1 transgenes develop A[3 amyloidosis. Significantly, the double mutants develop behavioral deficits. To illustrate how knock out strategies can validate therapeutic targets, we describe work in which we targeted genes encoding critical pro-amyloidogenic secretases, focusing on BACE1. Both in vitro and in vioo studies demonstrates that this enzyme is the neuronal [3-secretase. Moreover, mating strategies disclosed that APPswe; PSI 6E9:BACE1 - / - mice do not form any A[5 amyloid in brain. This research is consistent with the concept that BACE 1 is a principle determinant of formation of Af3 and, as such, has significant implications for the development of mechanism based therapies designed to prevent formation of A[3 in individuals with AD.

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neurobiology of cognitive dysfunction in schizophrenia: Insights from gene expression profiling

D.A. Lewis, K. Mimics, EA. Middleton, P. Levitt. University of Pittsburgh, Departments of Psychiatry and Neuroscience, Pittsburgh, PA, US.A. In subjects with schizophrenia, at least some of the cognitive deficits appear to be attributable to dysfunction of the dorsal prefrontal cortex (PFC). Assessment of gene expression in postmortem human tissue using microarrays provides a powerful approach to exploring the pathophysiology and pathogenesis of these cognitive deficits. Using cDNA microarrays, we have determined the expression levels of over 8000 genes and ESTs in PFC area 9 from matched pairs of schizophrenic and control subjects, and used complementary strategies for analyzing the results. One approach involved the identification of gene groups whose protein products contribute to specific functional cascades. Of the several hundred gene groups examined, those encoding proteins involved in presynaptic secretory machinery or in certain metabolic pathways were consistently under-expressed in subjects with schizophrenia, suggesting that disturbances in these functional cascades contribute to the pathophysiology of PFC dysfunction in schizophrenia. Another strategy involves the examination of changes in expression as a means for identifying candidate genes that may contribute to the primary pathogenesis of schizophrenia. For example, we found that the mRNA expression level of a regulator of G-protein signaling (RGS4) was consistently decreased in subjects with schizophrenia and that this alteration was present across multiple cortical regions, but that it was not altered in subjects with major depressive disorder or in monkeys treated chronically with antipsychotic medications. Interestingly, the RGS4 gene maps to chromosome lq21-22, a major susceptibility locus for schizophrenia, and our studies of over 1400 subjects revealed evidence of linkage and association between RGS4 polymorphisms and schizophrenia. These findings demonstrate the power of using gene expression profiling to discover the molecular, and possibly genetic, substrates for the types of cognitive disturbances that appear to represent core features of schizophrenia.

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Genetic strategies for dissecting the dopamine and related systems in ADHD and bipolar disorder

J.L. Kennedy, U. Jain, A. Petronis, P. Muglia. Neurogenetics Section, Clarke Site, Centre for Addiction and Mental Health, Toronto, Ontario M5T 1R8, Canada Attention deficit hyperactivity disorder (ADHD) is a prevalent psychiatric condition in children and follow up studies have indicated that 20 to 33% of patients continue to suffer from ADHD during late adolescence and adulthood. Convincing evidence supports the contribution of genetic factors in the etiology of ADHD, and the interaction of the psychostimulants with the dopamine system suggests that dopamine is involved in the pathophysiology. The adult ADHD variant represents a promising phenotype for studying the genetic component of the disorder. In fact, a recent familial study has shown that among relatives of ADHD patients that persist into adolescence there is a higher rate of ADHD (16.3%) compared to relatives of subjects that remit from ADHD