Journal of Neuroscience, Vol 14, 4196-4205, Copyright © 1994 by Society for Neuroscience
Kindling induces the long-lasting expression of a novel population of NMDA receptors in hippocampal region CA3
JE Kraus, GC Yeh, DW Bonhaus, JV Nadler and JO McNamara
Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710.
Kindling refers to a phenomenon in which repeated application of initially
subconvulsive electrical stimulations produces limbic and clonic motor
seizures of progressively increasing severity. Once established, the
increased excitability is lifelong. Enhanced function of synapses using the
NMDA subtype of glutamate receptor could contribute to the expression of
the increased excitability. We previously found that CA3 pyramidal cells of
hippocampus of kindled animals exhibit a selective and long-lasting (1
month) increased sensitivity to NMDA-evoked depolarization. The goal of
this study was to develop a molecular explanation of the enhanced
sensitivity to NMDA. We used radioligand binding studies of membranes
isolated from microdissected regions of hippocampus including fascia
dentata, CA3, and CA1. We also used quantitative in situ hybridization with
subtype- specific riboprobes or oligonucleotides to determine whether
increased expression of one or more of the genes encoding NMDA receptors
was present in hippocampal granule and pyramidal cells of kindled animals.
When studied 28 d after the last evoked seizure, we found that kindling
induced a 2.8-fold increase in the number of binding sites for the
competitive NMDA receptor antagonist 3-[(+/-)-2-(carboxypiperazine-4-
yl)][1,2-3H-]propyl-1-phosphonic acid (3H-CPP). This increase was confined
to region CA3 within the hippocampus. Similar, though much smaller, changes
were detected 24 hr after the last evoked seizure. Surprisingly, no changes
in the binding of another competitive NMDA receptor antagonist,
cis-4-(phosphonomethyl)-2-3H-piperidinecarboxylate (3H-CGS-19755), were
detected at either time point in any hippocampal region. Transcript levels
of the NMDA receptor genes NMDAR1, NR2A, NR2B, NR2C, and NR2D and a
glutamate-binding protein (GBP) were not altered by kindling. These
findings demonstrate that kindling induces the expression of an NMDA
receptor that is novel in that it is recognized by 3H-CPP but not by
3H-CGS-19755. The molecular basis of this novel NMDA receptor is not
determined by differential expression of mRNA transcripts of known NMDA
receptor genes. The direction, time course, and location of the
kindling-induced increase in 3H-CPP binding suggest that this novel
receptor may underlie the increased sensitivity of CA3 neurons to NMDA
observed in kindled animals.
Previous Article | Next Article
