This cross-species translational research program will use laboratory-based inhibitory biomarkers (IBs) to understand the genetic and neurobiological basis for the "group of schizophrenias." The overarching goal of this project is to identify genetic variation associated with deficits in specific IBs in schizophrenia patients, and in parallel, to use animal model studies to clarify the neurobiological mechanisms linking these genes and IB deficits, i.e. the "gene-to-phene gap." In schizophrenia patients and normal comparison subjects, measures will assess 3 extensively studied primary IBs with known schizophrenia-linked deficits - prepulse inhibition of startle (PPI), startle habituation (HAB), and event related potentials (ERPs). IBs, their interrelationships, and associations with demographic, clinical, neurocognitive and functional outcomes will be examined. In mice and rats, PPI, HAB, and ERPs will be measured.
In Aim 1, haplotype analyses will refine our preliminary IB-gene results. The genetic architecture of each IB in schizophrenia patients will be examined, focusing on 3 genes - NRG1;ERBB4;and COMT - together with other secondary genes of interest, based on preliminary association findings and/or the extant literature. Gene path analyses will more clearly define gene-gene interactions underlying biomarker-defined subgroups.
Aim 2 will test 400 new schizophrenia patients and 400 new normal comparison subjects. These 800 new subjects will provide the power necessary to conduct the proposed behavioral and genetic analyses. Fine mapping will be performed to clarify the genetic substrates of biomarkers using the inclusive sample as well biomarker-defined subgroups based on the extreme deciles and quartiles of the distribution of IB measures.
In Aim 3, pharmacological and molecular studies in rodents will explicate novel genetic mechanisms underlying IB deficits by: 1) assessing the impact of neuregulin-1 fragments on the IB deficits induced by dopamine agonists and NMDA antagonists in rats and mice;2) assessing IB deficits in interneuron-specific ErbB4 "knock out" mice;and 3) characterizing "knock in" mice having Val/Val or Met/Met variants of the human COMT gene, complemented by regionally specific viral delivery of the COMT gene.
Aim 4 will characterize changes in brain regional gene expression in rat models with construct validity for IB deficits in schizophrenia patients: neonatal ventral hippocampal lesions (NVHLs) and isolation rearing. RT-PCR studies in inbred rats will focus on genes found in preliminary cross-species studies to be associated with IB deficits (e.g. NRG1, ERBB4, COMT, GRID2, REELIN, and GRIN2B). Functional (neurochemical) consequences of differences in regional gene expression will also be confirmed in NVHL and isolation-reared rats. In aggregate, these 4 Aims will leverage powerful translational strategies to identify genes associated with IB deficits in schizophrenia patients, and to explicate the neurobiological mechanisms that mediate these associations.

Public Health Relevance

This application will use cross-species, translational studies to identify genes associated with deficits in specific brain-based inhibitory measures in patients with schizophrenia, and will identify the neurobiological mechanisms responsible for these deficits. The proposed studies extend the long-standing UCSD Schizophrenia Research Program work that has pioneered the use of laboratory-based biomarkers in order to better understand the clinical, cognitive, and everyday functional deficits of schizophrenia patients. By understanding the genetic and neural substrates of schizophrenia, new strong inference-based and personalized treatments can be identified for this devastating and costly disorder.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Meinecke, Douglas L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
Schools of Medicine
La Jolla
United States
Zip Code
Light, Gregory A; Swerdlow, Neal R; Thomas, Michael L et al. (2015) Validation of mismatch negativity and P3a for use in multi-site studies of schizophrenia: characterization of demographic, clinical, cognitive, and functional correlates in COGS-2. Schizophr Res 163:63-72
Tsuang, Debby; Esterberg, Michelle; Braff, David et al. (2014) Is there an association between advanced paternal age and endophenotype deficit levels in schizophrenia? PLoS One 9:e88379
Schmeidler, James; Lazzeroni, Laura C; Swerdlow, Neal R et al. (2014) Paternal age of schizophrenia probands and endophenotypic differences from unaffected siblings. Psychiatry Res 219:67-71
van Enkhuizen, Jordy; Henry, Brook L; Minassian, Arpi et al. (2014) Reduced dopamine transporter functioning induces high-reward risk-preference consistent with bipolar disorder. Neuropsychopharmacology 39:3112-22
Gresack, Jodi E; Seymour, Patricia A; Schmidt, Christopher J et al. (2014) Inhibition of phosphodiesterase 10A has differential effects on dopamine D1 and D2 receptor modulation of sensorimotor gating. Psychopharmacology (Berl) 231:2189-97
Young, Jared W; Ratty, Anil; Dawe, Gavin S et al. (2014) Altered exploration and sensorimotor gating of the chakragati mouse model of schizophrenia. Behav Neurosci 128:460-7
Braff, David L (2014) Genomic substrates of neurophysiological endophenotypes: where we've been and where we're going. Psychophysiology 51:1323-4
Perez, Veronica B; Swerdlow, Neal R; Braff, David L et al. (2014) Using biomarkers to inform diagnosis, guide treatments and track response to interventions in psychotic illnesses. Biomark Med 8:9-14
Risbrough, Victoria; Ji, Baohu; Hauger, Richard et al. (2014) Generation and characterization of humanized mice carrying COMT158 Met/Val alleles. Neuropsychopharmacology 39:1823-32
Light, Gregory; Greenwood, Tiffany A; Swerdlow, Neal R et al. (2014) Comparison of the heritability of schizophrenia and endophenotypes in the COGS-1 family study. Schizophr Bull 40:1404-11

Showing the most recent 10 out of 236 publications