Schizophrenia (SCZ) is a devastating disease that affects approximately 1% of the world's population and is characterized by a constellation of symptoms that include hallucinations and delusions (positive symptoms), antisocial behavior and blunted emotions (negative symptoms), deficits in working memory, executive function, and learning and memory (cognitive symptoms). The mechanisms underlying these symptoms remain unknown, mostly due to the lack of valid experimental approaches to model this disease. The 22q11.2-deletion syndrome (22q11DS), also known as velocardiofacialsyndrome or DiGeorge syndrome, is the most common microdeletion syndrome in humans. SCZ arises in approximately 30% of patients with 22q11DS during their adolescence or early adulthood. Mouse models of 22q11DS have been constructed and validated by replicating deficits in working memory, learning and memory, and other symptoms. Using these mutant mice, we and others have identified cellular and molecular mechanisms underlying the cognitive symptoms of 22q11DS. However, self-reported symptoms such as hallucinations cannot be convincingly modeled in mice. In this application, we propose to test the predictions of several recent neuroscience theories and human imaging data that hallucinations result from deficiencies in thalamocortical (TC) pathways that project to the sensory cortices. In our preliminary experiments in brain slices and in vivo, we found that mouse models of 22q11DS have substantial deficits in synaptic transmission and short-term plasticity at TC pathways to the auditory cortex. In this proposal, we will use single-cell electrophysiology, 2-photon imaging, 2-photon glutamate uncaging, optogenetics, and molecular tools to identify the cellular and molecular mechanisms of TC deficiencies in mouse models of 22q11Ds. Using multiple available strains of mutant mice that carry deletions of clusters of genes or individual genes that map within the large 22q11 microdeletion, we will identify the gene(s) whose deletion underlies TC deficits in these mice. We will also perform in vivo 2-photon imaging to observe abnormal spontaneous activity in individual neurons of the auditory cortex. Abnormal neuronal activity in the auditory cortex has been reported in patients who experience auditory hallucinations, which are most predominant in SCZ. Ultimately, we expect to identify the culprit gene(s) and synaptic targets that cause TC abnormalities and abnormal cortical activity in these mouse models of SCZ. This information will provide a framework for the future development of specific therapeutic interventions to alleviate positive symptoms in patients with this catastrophic disease.

Public Health Relevance

The cause and mechanisms of schizophrenia are mostly unknown. Heterozygous deletions within the 22q11 chromosome cause 22q11.2-deletion syndrome (22q11DS) and substantially increase an individual's risk of schizophrenia. Theoretical works have proposed that thalamocortical pathway deficiencies are the underlying mechanisms of hallucinations, a positive symptom of the disease. In schizophrenia and 22q11DS, positive symptoms are responsive to treatment with antipsychotic drugs. In preliminary studies, we found that mouse models of 22q11DS have deficits in thalamocortical pathways, and these deficits are rescued by antipsychotics. To better understand the mechanisms of 22q11DS and schizophrenia, we will investigate the cause and mechanisms of deficits in thalamocortical pathways in mutant mice that model these catastrophic diseases.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-P (57))
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Meinecke, Douglas L
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St. Jude Children's Research Hospital
United States
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Chun, Sungkun; Westmoreland, Joby J; Bayazitov, Ildar T et al. (2014) Specific disruption of thalamic inputs to the auditory cortex in schizophrenia models. Science 344:1178-82
Earls, Laurie R; Westmoreland, Joby J; Zakharenko, Stanislav S (2014) Non-coding RNA regulation of synaptic plasticity and memory: implications for aging. Ageing Res Rev 17:34-42