Patients with schizophrenia exhibit behavioral and physiological impairments in the perception, modulation and evaluation of environmental stimuli. These information-processing deficits disrupt patients'efforts to detect, interpret and assign salience to incoming stimuli, resulting in disturbed behavioral responses. Clinically, this can result in hallucinations, ideas of reference, impaired affective expression and abnormal social interactions. Although memory deficits are among the most obvious and pervasive cognitive mpairments in schizophrenia, there is a growing body of evidence that very early elements of information processing, including perceptual integration and deviance detection, are also disrupted. Results of previous CCNMD event-related potential (ERP) studies demonstrated that: 1) deficits in early sensory processes contribute substantially to the deficits observed in later cognitive operations;2) early sensory deficits are evident in both the auditory and visual sensory systems;3) early sensory deficits are indicators of genetic vulnerability to schizophrenia. Animal and post-mortem studies suggested that genetically-mediated disturbances in glutamatergic transmission and synaptic function contribute to these ERP abnormalities. The current proposal will build upon these initial findings by further delineating the nature and etiology of deficits in early stimulus encoding and deviance detection. Patients, unaffected family members and healthy controls (80 subjects / group) will be studied using experimental protocols and analytic methods designed to assess the contributions of gamma and theta oscillations to these sensory processing disturbances. Evoked and induced gamma and theta rhythms constitute fundamental mechanisms for feature recognition and context-sensitive processing of sensory information, and are mediated by synaptic activity in the neural structures and transmitter systems implicated in schizophrenia. To determine the contribution of specific genetic vulnerability factors to these neural abnormalities, subjects will be categorized with respect to highrisk haplotypes for three genes that have been implicated in schizophrenia and that modulate pre- or postsynaptic glutamatergic neurotransmission or intracellular signaling: dysbindin (DTNBP1), neuregulin (NRG1) and RGS4. These studies will increase understanding of the brain abnormalities that underlie the cognitive impairments of schizophrenia. This, in turn, could provide the basis for developing new types of treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH064045-10
Application #
8118814
Study Section
Special Emphasis Panel (ZMH1)
Project Start
2010-08-01
Project End
2011-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
10
Fiscal Year
2010
Total Cost
$171,805
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
van Erp, Theo G M; Walton, Esther; Hibar, Derrek P et al. (2018) Cortical Brain Abnormalities in 4474 Individuals With Schizophrenia and 5098 Control Subjects via the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) Consortium. Biol Psychiatry 84:644-654
Walton, E; Hibar, D P; van Erp, T G M et al. (2017) Positive symptoms associate with cortical thinning in the superior temporal gyrus via the ENIGMA Schizophrenia consortium. Acta Psychiatr Scand 135:439-447
Barz, Claudia S; Bessaih, Thomas; Abel, Ted et al. (2016) Sensory encoding in Neuregulin 1 mutants. Brain Struct Funct 221:1067-81
Satterthwaite, Theodore D; Wolf, Daniel H; Calkins, Monica E et al. (2016) Structural Brain Abnormalities in Youth With Psychosis Spectrum Symptoms. JAMA Psychiatry 73:515-24
Welle, Cristin G; Contreras, Diego (2016) Sensory-driven and spontaneous gamma oscillations engage distinct cortical circuitry. J Neurophysiol 115:1821-35
Satterthwaite, Theodore D; Connolly, John J; Ruparel, Kosha et al. (2016) The Philadelphia Neurodevelopmental Cohort: A publicly available resource for the study of normal and abnormal brain development in youth. Neuroimage 124:1115-9
Barz, Claudia S; Bessaih, Thomas; Abel, Ted et al. (2016) Altered resonance properties of somatosensory responses in mice deficient for the schizophrenia risk gene Neuregulin 1. Brain Struct Funct 221:4383-4398
Collier, Azurii K; Wolf, Daniel H; Valdez, Jeffrey N et al. (2014) Comparison of auditory and visual oddball fMRI in schizophrenia. Schizophr Res 158:183-8
Robinson, John L; Molina-Porcel, Laura; Corrada, Maria M et al. (2014) Perforant path synaptic loss correlates with cognitive impairment and Alzheimer's disease in the oldest-old. Brain 137:2578-87
Larimore, Jennifer; Zlatic, Stephanie A; Gokhale, Avanti et al. (2014) Mutations in the BLOC-1 subunits dysbindin and muted generate divergent and dosage-dependent phenotypes. J Biol Chem 289:14291-300

Showing the most recent 10 out of 118 publications