Project 2 — Morphological alterations of cortical layer 3 pyramidal cells in schizophrenia
Individuals with schizophrenia have impairments in attention and working memory, the ability to retain information in mind, which are important determinants of day-to-day function. This project will determine if individuals with schizophrenia have impairments in the neuronal structures in three key brain regions that form the circuits responsible for attention and working memory.
Robert A. Sweet, MD
Kenneth N. Fish, PhD
Assistant Professor, Psychiatry
David A. Lewis, MD
UPMC Professor in Translational Neuroscience, Psychiatry and Neuroscience
The Center's Central Hypothesis posits that layer 3 pyramidal cells (PCs) in subjects with schizophrenia have a cell type-autonomous pathology that is reflected in altered somatodendritic morphology and that differs in severity across regions in the cortical visual working memory and attention network. These abnormalities of layer 3 PCs result in locally reduced excitatory drive, reflected in reduced markers of metabolic activity in layer 3 PCs and reduced activity-dependent markers in reciprocally-connected layer 3 parvalbumin (PV)-expressing basket cells. This model leads to several novel predictions. For example, that deficits in layer 3 PC somal volume and dendritic spine density are present in multiple cortical regions, but moderated by region-specific factors (Aim 1). To date only limited analyses of primary visual cortex (V1) have been conducted, and the posterior parietal cortex (PPC) has not been examined. Our preliminary data indicate that impairments in dorsolateral prefrontal cortex (DLPFC) are associated with reduced markers of local network activity within PCs and PV basket cells. Functional data indicate impaired activity within V1 and PPC during visual tasks in subjects with schizophrenia. Thus, our model predicts that markers of neuronal activity are also altered within V1 and PPC (Aim 2). Finally, reductions in pre-synaptic proteins such as synaptophysin and synapsin1, that are known to impair glutamatergic bouton function, behavior, and cognition, have been previously observed in schizophrenia. Our model predicts that reductions in these proteins predominate in intracortical glutamatergic boutons within layer 3 across V1-PPC-DLPFC and are positively correlated with the magnitude of the underlying somatodendritic abnormalities within regions in the network (Aim 3). This project serves as an essential link between disease-related molecular findings in these same neurons, layers and regions (Project 1) and abnormal information processing in disease (Project 5). This project will constrain the interpretation of how normative functional connectivity (Projects 4 & 5) is altered in disease (Project 5) and will guide predictions for future studies using markers specific for projections between PPC and DLPFC that may be identified in Project 3.
|Project: 1 2 3 4 5 Statistics Core|
Silvio O. Conte Center for Translational Mental Health Research
Funded by the National Institute of Mental Health (MH103204)