GLUTAMATE CURRENTS IN MORPHOLOGICALLY IDENTIFIED HUMAN DENTATE GRANULE
CELLS IN TEMPORAL LOBE EPILEPSY.
Masako Isokawa, Michel Levesque, Itzhak Fried and Jerome Engel.
Brain Research Institute1, Departments of Neurology 2 and Neurosurgery 3,
Center for Health Sciences, University of California, Los Angeles, CA 90024-
1761.
APStracts 4:0060N, 1997.
ABSTRACT
Glutamate receptor-mediated synaptic transmission was studied in
morphologically-identified hippocampal dentate granule cells (N=31) with the
use of whole-cell patch clamp recording and intracellular injection of
biocytin or Lucifer yellow in slices prepared from surgically-removed medial
temporal lobe specimens of epileptic patients (14 specimens from 14 patients).
In the current clamp recording, a low frequency stimulation of the perforant
path generated depolarizing postsynaptic potentials (DPSPs) that consisted of
excitatory postsynaptic potentials and phase-inverted inhibitory postsynaptic
potentials mediated by the GABAA receptor at a resting membrane potential of -
62.7 mV 2.0 SEM. In the voltage-clamp recording, two glutamate conductances,
a fast AMPA receptor-mediated EPSC (AMPA EPSC) and a slowly-developing NMDA
receptor-mediated EPSC (NMDA EPSC), were isolated in the presence of a GABAA
receptor antagonist. NMDA EPSCs showed a voltage-dependent increase in
conductance with depolarization by exhibiting an N-shaped current-voltage
relationship. The slope conductance of the NMDA EPSC ranged from 1.1 to 9.4 nS
in 31 DGCs, reaching up to twice the size of the AMPA conductance. This
widely-varying size of the NMDA conductance resulted in the generation of
double-peaked EPSCs and a non-linear increase of its slope conductance with
positive membrane potentials of up to 37.5 nS, which resembled "paroxysmal
currents", in a subpopulation of the neurons. In contrast, AMPA EPSCs, which
were isolated in the presence of an NMDA receptor antagonist (APV), showed
voltage-independent linear changes in the current-voltage relationship and
were blocked by CNQX. The AMPA conductance showed little variance, regardless
of the size of the NMDA conductance of a given neuron. The average AMPA slope
conductance was 5.28 nS 0.65 SEM in 31 human DGCs. This value was similar to
AMPA EPSC conductances in normal rat dentate granule cells (5.35 nS 0.52 SEM;
N=55). Dendritic morphology and spine density were quantified in the
individual DGCs in order to assess epileptic pathology. Dendritic spine
density showed an inverse correlation (r2=0.705) with a slower rise time and a
longer half-width of the EPSPs mediated by the NMDA receptor. It is concluded
that both AMPA and NMDA EPSCs contribute to human DGC synaptic transmission in
epileptic hippocampus. However, a wide range of changes in the slope
conductance of the NMDA EPSCs suggest that the NMDA receptor-mediated
conductance could be altered in human epileptic DGCs. These changes may
influence the generation of chronic sub-threshold epileptogenic synaptic
activity and give rise to pathological excitation leading to epileptic
seizures and dendritic pathology.
Received 7 June 1996; accepted in final form 4 February 1997.
APS Manuscript Number J456-6.
Article publication pending J. Neurophysiol.
ISSN 1080-4757 Copyright 1997 The American Physiological Society.
Published in APStracts on 20 February 1997