Schizophrenic patients show high-level olfactory deficits that may be caused, at least in part, by structural alterations in olfactory cortex and its connections. Our group has studied animal models relevant to the structural plasticity of the rodent primary olfactory (piriform) cortex for a decade and has established lesion and genetic models to study piriform cortex remodeling. The central hypothesis of this proposal is that BACE1- neuregulin 1 (NRG1)-ErbB4 signaling is critical for the ongoing remodeling of piriform cortex, primarily by affecting the induction and differentiation of basal forebrain neurogenic niches and that perturbations of these processes may cause some of the clinical manifestations of schizophrenia. The principal mechanism explored here is the activation and/or induced migration of GABAergic interneurons of layer I, especially evident after olfactory lesions. These interneurons then lay the groundwork for reconstitution of the pyramidal layer of piriform cortex.
In Specific Aim 1, we establish the role of BACE1- NRG1 in the development and lesion- induced plasticity (remodeling) of piriform cortex.
In Aim 2, we explore specific cellular and molecular mechanisms of piriform remodeling involving GABAergic interneurons and neurogenic niches in the basal forebrain. Together, experiments proposed here link NRG1 signaling pathways with GABAergic cortical interneurons in animal models relevant to schizophrenia.
Schizophrenia is a debilitating mental illness whose causes and mechanisms have been very difficult to decipher. A major problem in the past was the absence of animal models in which to alter the expression of genes or make lesions and then follow behaviors and study biological links (mechanisms) between interventions and outcomes. This significant obstacle is now starting to yield, with the discovery of susceptibility genes that contribute to the disease cause and the availability of transgenic animals with altered expression of these genes or their downstream molecular targets. In this application, we combine our traditional strengths in neural plasticity of the olfactory limbic system and in transgenic animal models and propose that at least a portion of psychotic symptoms may be modeled on the basis of a stalled plasticity of the olfactory cortex and its connections because of deficient signals in GABAergic cortical interneurons.
| Rossi, Sharyn L; Mahairaki, Vasiliki; Zhou, Lijun et al. (2014) Remodeling of the piriform cortex after lesion in adult rodents. Neuroreport 25:1006-12 |
