PT  - JOURNAL ARTICLE
AU  - Cao, Zhengyu
AU  - Cui, Yanjun
AU  - Nguyen, Hai M.
AU  - Jenkins, David Paul
AU  - Wulff, Heike
AU  - Pessah, Isaac N.
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 Jan 01
TA  - Molecular Pharmacology
PG  - mol.113.090076
4099  - http://molpharm.aspetjournals.org/content/early/2014/01/30/mol.113.090076.short
4100  - http://molpharm.aspetjournals.org/content/early/2014/01/30/mol.113.090076.full
AB  - Bifenthrin, a relatively stable type I pyrethroid that causes tremors and impairs motor activity in rodents, is broadly used. Whether nanomolar bifenthrin alters synchronous Ca2+ oscillations (SCO) necessary for activity dependent dendritic development was investigated. Primary mouse cortical neurons were cultured 8-9 days in vitro (DIV), loaded with the Ca2+ indicator Fluo-4, and imaged using FLIPR Tetra. Acute exposure to bifenthrin rapidly increased the frequency of SCO 2.7-fold (EC50=58nM) and decreased SCO amplitude by 36%. Changes in SCO properties were independent of modifications in voltage-gated sodium channels since 100nM bifenthrin had no effect on the whole-cell Na+ current, nor influenced neuronal Erest. The L-type Ca2+ channel blocker nifedipine failed to ameliorate bifenthrin-triggered SCO activity. By contrast, the mGluR 5 antagonist MPEP normalized bifenthrin-triggered increase in SCO frequency without altering baseline SCO activity, indicating that bifenthrin amplifies mGluR 5 signaling independent of Na+ channel modification. Competitive (AP-5) and non-competitive (MK801) NMDAR 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). Sub-acute (48h) 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 mGluR 5 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.