While cognitive dysfunction is considered one of the more debilitating symptoms of schizophrenia, currently available antipsychotic drugs appear to have relatively minor effects on cognition. Our long-term goal is to develop better therapeutic modalities that target the known pathophysiology of schizophrenia. BDNF is a known regulator of GABA system and both BDNF and GABA systems have been shown to be disrupted in schizophrenia. Thus, enhancing BDNF signaling may offer the potential to ameliorate GABA deficits in schizophrenia. Our recent studies demonstrate that Cysteamine (an aminothiol degradation product of cysteine used clinically for the treatment of cystinosis) prevents haloperidol-induced reduction in BDNF/TrkB signaling in mouse prefrontal cortex (PFC), and it also increases GAD67 protein expression through TrkB signaling in cortical neurons. While these preliminary observations are interesting, more experiments are necessary to understand whether the changes induced by Cysteamine on GABA system are functional. To this end, we propose the following experiments using heterozygous reeler mice, which have decreased GAD67 expression and TrkB signaling, in addition to many behavioral and neuroanatomical abnormalities homologous to schizophrenia. First, we will test the hypothesis that TrkB is expressed on GAD67-positive neurons in heterozygous reeler mice. We will determine the colocalization of TrkB and GAD67 in PFC, hippocampus, striatum and cerebellum. We will also determine the association of GAD67 with TrkB and BDNF in the above brain regions. Second, we will test the hypothesis that Cysteamine treatment enhances GAD67 expression and improves cognitive function in heterozygous reeler mice. We will determine the effect of Cysteamine treatment on PPI (pre-attentive processing) and Y-maze spontaneous alternation and novel arm tasks (spatial working and short term memory) in heterozygous and wild-type (WT) mice. We will also determine the effects of Cysteamine treatment on mRNA and protein expression of reelin, BDNF, TrkB and GABA synthesizing enzymes (GAD65 and GAD67) in PFC, hippocampus, striatum and cerebellum of heterozygous and WT mice after cognitive function tests. It is our hope that Cysteamine by improving BDNF signaling (and, as a result, GABA function) will improve cognitive deficits that are commonly observed in schizophrenia. The results from this exploratory study (R03) will serve as a proof of concept for the development a novel (pathophysiology- based) therapeutic approach for schizophrenia.
This application will explore the role of brain derived neurotrophic factor (a key brain chemical supporting cell development/repair)-mediated pathway as a treatment strategy for schizophrenia.
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|Howell, Kristy R; Pillai, Anilkumar (2014) Effects of prenatal hypoxia on schizophrenia-related phenotypes in heterozygous reeler mice: a gene × environment interaction study. Eur Neuropsychopharmacol 24:1324-36|
|Pandya, Chirayu D; Howell, Kristy R; Pillai, Anilkumar (2013) Antioxidants as potential therapeutics for neuropsychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 46:214-23|
|Howell, Kristy R; Hoda, Md Nusrul; Pillai, Anilkumar (2013) VEGF activates NR2B phosphorylation through Dab1 pathway. Neurosci Lett 552:30-4|
|Kutiyanawalla, Ammar; Promsote, Wanwisa; Terry, Alvin et al. (2012) Cysteamine treatment ameliorates alterations in GAD67 expression and spatial memory in heterozygous reeler mice. Int J Neuropsychopharmacol 15:1073-86|