Role of astroglia in major depression
Principal Investigator: Prabhakara Choudary, Ph.D.
Multiple lines of recent evidence implicate glial cells in the etiology of major depression. For example, lowered astrocyte counts have been documented in the frontal cortex, in regions important for cognition, mood and motivation. Neuroimaging studies and postmortem histological and morphometric studies of depressed individuals who died young by suicide suggest a possible role for astroglia. Yet, hypotheses concerning depression etiology dogmatically approach major depression as a disorder of neurons, and ignore glia. To resolve this paradox, we profiled gene expression pattern in postmortem frontal cortex of depressed individuals using high density oligonucleotide microarrays. To our dismay, we found significant downregulation of glutamatergic genes, e.g., glial high-affinity glutamate transporters (SLC1A2 and SLC1A3) and glutamine synthetase (GS), concomitant with upregulation of the genes encoding glutamate (NMDA) and GABA receptor subunits (GABA-A receptor α1 and GABA-A receptor β3). These results provide further compelling evidence for the role of astroglia in major depression, since astrocytes are the site of biosynthesis of SLC1A2, SLC1A3 and GS. They also raise several tantalizing questions, e.g., (i) what changes in these genes (DNA) cause their transcript levels to drop?; (ii) do translational changes corroborate the transcriptional changes observed?; and (iii) will these genes potentially be useful as biomarkers of major depression? We are addressing these questions using a variety of tools and techniques, including: Laser Capture Microdissection (LCM); miRNA; and immunochemical and biological assays of functional activities. We anticipate the results will lead to the development of early detection screens with increased sensitivity and specificity. Similarly, the abnormal molecules/ circuits identified here could serve as targets for novel drugs, e.g., NMDA receptor antagonists or agents that can selectively restore the balance between inhibitory and excitatory synaptic transmission, and curtail excessive excitatory activity, ushering in an era of pathophysiological mechanism-targeted rather than symptom-based therapeutics. These studies are a part of an interdisciplinary multi-investigator study, carried out in close collaboration with fellow members of the Conte Center and Pritzker Consortium (of five US universities).
Engrailed2 regulates forebrain monoamines and behavior
Engrailed2 is a homeodomain transcription factor that regulates embryonic hindbrain development. Single nucleotide polymorphisms in EN2, the gene coding for Engrailed2, have been associated with autism in five independent genetic studies, implicated EN2 genetic variants as a likely autism susceptibility gene. This project investigates monoamine levels and behavioral phenotypes relevant to the symptoms of autism in En2 knockout mice. We are conducting behavioral assays relevant to sociability, cognition, and depression. Pharmacological treatments that reverse the noradrenergic abnormalities discovered by our collaborator Manny DiCicco-Bloom are being evaluated for reversal of behavioral phenotypes in En2 knockout mice.
Genetics and physiology of emotion in Fragile X syndrome
Principal Investigator: David Hessl, Ph.D.
This research investigates genetic, physiological, and environmental factors that contribute to emotional problems in individuals with Fragile X syndrome, and in carriers of the Fragile X mental retardation 1 (FMR1) gene. In addition to cognitive impairment, children and adults with Fragile X syndrome demonstrate a characteristic behavioral phenotype that includes prominent social anxiety and avoidance. Using psychophysiological measures including potentiated startle reflex, electrodermal response, and cardiovascular reactivity, we are examining the biological basis of these difficulties. Given that many individuals with Fragile X also have autism, we are especially interested in knowing whether physiological reactivity contributes to deficits in reciprocal social interaction in these individuals. In addition, in collaboration with other member of the Fragile X team at U.C. Davis, we are studying variation in other genes including the monoamine oxydase A and serotonin transporter polymorphisms as well as environmental factors that may explain variation in the severity of the behavioral phenotype. Finally, related work in the laboratory focuses on limbic system function in adult premutation carriers in collaboration with Drs. Rivera, Tassone, and Hagerman. We have recently established that male carriers with abnormal elevation of FMR1 mRNA report higher rates of psychological symptoms. We are seeking to understand the brain basis of these symptoms, and the relevance of these findings to the Fragile X-Associated Tremor Ataxia Syndrome, which occurs in older male and rare female carriers.
Immune system regulation of neural stem cells in the prenatal brain
Principal Investigator: Stephen C. Noctor, Ph.D.
Recent studies show that microglia, the immune cell component of the central nervous system, colonize neural stem cell niches and regulate cell production in proliferative regions of the prenatal brain. The goal of this project is to identify the signaling pathways that regulate interactions between microglia and neural stem cells in the developing brain under normal and pathological conditions. This project will contribute to our understanding of the etiology of neurodevelopmental disorders, such as schizophrenia and autism, in which immune system activation during gestation has been implicated.