Neurophysiologic effects of chemical agent hydrolysis products on corticalneurons in vitro

The neurophysiologic effects of chemical agent hydrolysis products were exa mined on cultured cortical neurons using multielectrode array (MEA) recordi ng and the whole-cell patch clamp technique. Measurements of neuronal netwo rk extracellular potentials showed that the primary hydrolysis product of s oman, pinacolyl methylphosphonic acid (PMPA), inhibited network mean burst and spike rates with an EC50 of approximately 2 mM. In contrast, the degrad ation product of sarin, isopropyl methylphosphonic acid (IMPA), and the fin al common hydrolysis product of both soman and sarin, methylphosphonic acid (MPA), failed to affect neuronal network behavior at concentrations reachi ng 5 mM. Closer examination of the effects of PMPA (2 mM) on discriminated extracellular units revealed that mean spike amplitude was slightly diminis hed to 95 +/- 1% (mean +/- S.E.M., n = 6, P < 0.01) of control. Whole-cell patch clamp records under current clamp mode also showed a PMPA-induced dep ression of the firing rate of spontaneous action potentials (APs) to 36 +/- 6% (n = 5. P < 0.001) of control. In addition, a minor depression with exp osure to PMPA was observed in spontaneous and evoked AP amplitude to 93 +/- 3% (n = 5, P < 0.05) of control with no change in either the baseline memb rane potential or input resistance. Preliminary voltage clamp recordings in dicated a reduction in the occurrence of spontaneous inward currents with a pplication of PMPA. These findings suggest that PMPA, unlike MPA or IMPA, m ay more readily interfere with one or more aspects of excitatory synaptic t ransmission. Furthermore, the data demonstrate that the combination of extr acellular microelectrode array and patch clamp recording techniques facilit ates analysis of compounds with neuropharmacologic effects. (C) 2001 Publis hed by Elsevier Science Inc.