Synaptic activity can encode and store information in the brain through changes in synaptic strength as well as by control of gene expression. One corollary challenge becomes identifying these activity-dependent regulatory proteins and the underlying mechanisms associated with neuronal functions. By using biochemical, electrophysiological and behavioral approaches in combination with genetic and pharmacological manipulation, I report that LIM domain only 4 (LMO4) is a key regulator of calcium induced calcium release (CICR) and protein tyrosine phosphatase 1B (PTP1B) in the hippocampus and amygdala, respectively. Neuronal ablation of LMO4 in the glutamatergic neurons (LMO4KO) was associated with reduced promoter activity, mRNA, and protein expression of ryanodine receptor 2 (RyR2), suggesting the involvement of LMO4 in the transcriptional regulation. CICR function in LMO4KO mice was severely compromised, reflected by inefficient CICR-mediated electrophysiological responses including afterhyperpolarization, calcium rise from internal stores and glutamate release probability. These changes were accompanied with impaired hippocampal long term potentiation (LTP) and hippocampal-dependent spatial learning ability. LMO4 was also shown to exert a cytoplasmic regulation as an endogenous inhibitor for PTP1B that accounts for tyrosine dephosphorylation of mGluR5 in the amygdala. LMO4KO mice had elevated PTP1B activity and decreased mGluR endocannabinoid signaling, resulting in a profound anxiety phenotype. The potential clinical value of PTP1B/LMO4 is promising, given that intra-amygdala injection of the PTP1B inhibitor Trodusquemine or a PTP1B shRNA alleviated anxiety by restoring eCB signal in LMO4KO mice. Thus this study identified PTP1B as a potential therapeutic target for anxiety, besides the previous findings of its association with obesity and diabetes. Moreover, this PTP1B-mediated anxiety may be a general mechanism during chronic stress. Collectively, these findings identify that LMO4 plays an essential role for non-genomic and genomic regulation in central neurons, providing a mechanism for LMO4 to modulate a wide range of neuronal functions and behavior.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/26204 |
| Date | January 2013 |
| Creators | Qin, Zhaohong |
| Contributors | Chen, Hsiao-Huei, Beïque, Jean-Claude |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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