PT - JOURNAL ARTICLE AU - Zhengyu Cao AU - Yanjun Cui AU - Hai M. Nguyen AU - David Paul Jenkins AU - Heike Wulff AU - Isaac N. Pessah TI - Nanomolar Bifenthrin Alters Synchronous Ca<sup>2+</sup> Oscillations and Cortical Neuron Development Independent of Sodium Channel Activity AID - 10.1124/mol.113.090076 DP - 2014 Apr 01 TA - Molecular Pharmacology PG - 630--639 VI - 85 IP - 4 4099 - http://molpharm.aspetjournals.org/content/85/4/630.short 4100 - http://molpharm.aspetjournals.org/content/85/4/630.full SO - Mol Pharmacol2014 Apr 01; 85 AB - Bifenthrin, a relatively stable type I pyrethroid that causes tremors and impairs motor activity in rodents, is broadly used. We investigated whether nanomolar bifenthrin alters synchronous Ca2+ oscillations (SCOs) necessary for activity-dependent dendritic development. Primary mouse cortical neurons were cultured 8 or 9 days in vitro (DIV), loaded with the Ca2+ indicator Fluo-4, and imaged using a Fluorescence Imaging Plate Reader Tetra. Acute exposure to bifenthrin rapidly increased the frequency of SCOs by 2.7-fold (EC50 = 58 nM) and decreased SCO amplitude by 36%. Changes in SCO properties were independent of modifications in voltage-gated sodium channels since 100 nM bifenthrin had no effect on the whole-cell Na+ current, nor did it influence neuronal resting membrane potential. The L-type Ca2+ channel blocker nifedipine failed to ameliorate bifenthrin-triggered SCO activity. By contrast, the metabotropic glutamate receptor (mGluR)5 antagonist MPEP [2-methyl-6-(phenylethynyl)pyridine] normalized bifenthrin-triggered increase in SCO frequency without altering baseline SCO activity, indicating that bifenthrin amplifies mGluR5 signaling independent of Na+ channel modification. Competitive [AP-5; (−)-2-amino-5-phosphonopentanoic acid] and noncompetitive (dizocilpine, or MK-801 [(5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate]) N-methyl-d-aspartate antagonists partially decreased both basal and bifenthrin-triggered SCO frequency increase. Bifenthrin-modified SCO rapidly enhanced the phosphorylation of cAMP response element–binding protein (CREB). Subacute (48 hours) exposure to bifenthrin commencing 2 DIV–enhanced neurite outgrowth and persistently increased SCO frequency and reduced SCO amplitude. Bifenthrin-stimulated neurite outgrowth and CREB phosphorylation were dependent on mGluR5 activity since MPEP normalized both responses. Collectively these data identify a new mechanism by which bifenthrin potently alters Ca2+ dynamics and Ca2+-dependent signaling in cortical neurons that have long term impacts on activity driven neuronal plasticity.