title: LIM domain only 4 (LMO4) regulates calcium-induced calcium release and synaptic plasticity in the hippocampus.
abstract: The LIM domain only 4 (LMO4) transcription cofactor activates gene expression in neurons and regulates key aspects of network formation, but the mechanisms are poorly understood. Here, we show that LMO4 positively regulates ryanodine receptor type 2 (RyR2) expression, thereby suggesting that LMO4 regulates calcium-induced calcium release (CICR) in central neurons. We found that CICR modulation of the afterhyperpolarization in CA3 neurons from mice carrying a forebrain-specific deletion of LMO4 (LMO4 KO) was severely compromised but could be restored by single-cell overexpression of LMO4. In line with these findings, two-photon calcium imaging experiments showed that the potentiation of RyR-mediated calcium release from internal stores by caffeine was absent in LMO4 KO neurons. The overall facilitatory effect of CICR on glutamate release induced during trains of action potentials was likewise defective in LMO4 KO, confirming that CICR machinery is severely compromised in these neurons. Moreover, the magnitude of CA3-CA1 long-term potentiation was reduced in LMO4 KO mice, a defect that appears to be secondary to an overall reduced glutamate release probability. These cellular phenotypes in LMO4 KO mice were accompanied with deficits in hippocampus-dependent spatial learning as determined by the Morris water maze test. Thus, our results establish LMO4 as a key regulator of CICR in central neurons, providing a mechanism for LMO4 to modulate a wide range of neuronal functions and behavior.
authors.affiliation: Centre for Stroke Recovery, Neuroscience, Ottawa Hospital Research Institute; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Zhaohong
authors.initials: Z
authors.lastname: Qin
authors.forename: Xun
authors.initials: X
authors.lastname: Zhou
authors.forename: Mariana
authors.initials: M
authors.lastname: Gomez-Smith
authors.forename: Nihar R
authors.initials: NR
authors.lastname: Pandey
authors.forename: Kevin F H
authors.initials: KF
authors.lastname: Lee
authors.forename: Diane C
authors.initials: DC
authors.lastname: Lagace
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Béïque
authors.forename: Hsiao-Huei
authors.initials: HH
authors.lastname: Chen
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology*; D006825:Hybridomas; D060588:LIM Domain Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018691:Excitatory Amino Acid Antagonists; D060588:LIM Domain Proteins; C491976:Lmo4 protein, mouse; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D019837:Ryanodine Receptor Calcium Release Channel; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D002110:Caffeine; D016291:Dizocilpine Maleate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517671:Camk2a protein, mouse; D002118:Calcium