Background-General anesthetics (GAs) may exert harmful effects on the developing brain by disrupting neuronal circuit formation. Anesthetics that act on γ-aminobutyric acid (GABA) receptors can interfere with axonal growth cone guidance, a critical process in the assembly of neuronal circuitry. Here we investigate the mechanism by which isoflurane prevents sensing of the repulsive guidance cue, Semaphorin 3A (Sema3A). Methods-Growth cone sensing was assayed by measuring growth cone collapse in dissociated neocortical cultures exposed to recombinant Sema3A in the presence or absence of isoflurane and/or a panel of reagents with specific actions on components of the GABA receptor and chloride ion systems. Results-Isoflurane exposure prevents Sema3A induced growth cone collapse. A GABA A α2 specific agonist replicates this effect (36.83±3.417% vs 70.82±2.941%, in the Sema3A induced control group, p<0.0001), but an α1-specific agonist does not. Both a Na-K-Cl cotransporter 1 antagonism (bumetanide, BUM) and a chloride ionophore (IONO) prevent isoflurane from disrupting growth cone sensing of Sema3A. (65.67±3.775% in Iso+BUM group vs 67.45± 3.624% in Sema3A induced control group, 65.34±1.678% in Iso+IONO group vs 68.71± 2.071% in Sema3A induced control group, no significant difference) (n=96 growth cones per group). Conclusion-Our data suggest that the effects of isoflurane on growth cone sensing are mediated by the α2 subunit of the GABA A receptor and also that they are dependent on the
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