[Abstract Title]. - Society for Neuroscience

Title: Rotenone reduces Mg2+-dependent block of NMDA currents in substantia nigra dopamine
neurons
Authors: Y.-N. WU 1 , *S. W. JOHNSON 1,2 ;
1 Dept Neurol, Oregon Hlth. & Sci. Univ., Portland, OR; 2 Portland Veterans Affairs Med. Ctr.,
Portland, OR
Abstract: Rotenone is a pesticide that has been successfully used to produce a rodent model of
Parkinson‟s disease. We reported previously that rotenone potently augmented NMDA-evoked
currents in rat dopamine neurons via a tyrosine kinase-dependent mechanism. In this study, we
investigated the effect of rotenone on the current-voltage relationship of NMDA-induced
currents in substantia nigra zona compacta neurons recorded with whole-cell patch pipettes in
slices of rat brain. Currents were measured during a continuous voltage ramp from -120 to -
30mV (4s duration). In a physiologic concentration of Mg2+ (1.2mM), a 30min perfusion with
rotenone (100nM) produced marked increases in NMDA currents especially when measured at
relatively hyperpolarized currents. At -100mV, for example, NMDA (20µM) evoked 819±50pA
of inward current in the presence of rotenone compared to 288±39pA in control conditions. In
the presence of rotenone, NMDA currents lost the characteristic region of negative slope
conductance that is normally produced by voltage-dependent block by Mg2+. In the presence of
0.2mM Mg2+, NMDA produced 1338±125pA of inward current at -110mV, and this current was
not significantly increased after 30min perfusion with rotenone (1638±134pA). Furthermore, an
elevated extracellular concentration of Mg2+ (6mM) nearly completely blocked the ability of
rotenone to potentiate NMDA-induced inward currents. Voltage-dependent augmentation of
NMDA currents by rotenone was blocked by the tyrosine kinase inhibitor genistein (100µM).
These results suggest that rotenone potentiates NMDA currents by a tyrosine kinase-dependent
process that attenuates voltage-dependent Mg2+ block of NMDA-gated channels. In that
augmentation of NMDA-gated channels may mediated some aspects of neurotoxicity, our data
suggests that elevated levels of Mg2+ might be neuroprotective in animal models of Parkinson‟s
disease.
Disclosures: Y. Wu, None; S.W. Johnson , None.
Poster
253. Parkinson's Disease Models: Neuroprotective Mechanisms I
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 253.9/X10
Topic: C.11.j. Neuroprotective mechanisms: Parkinson‟s disease models
Support: Davis Phinney Foundation