Tonic Facilitation of Glutamate Release by Presynaptic NR2B-Containing NMDA Receptors Is Increased in the Entorhinal Cortex of Chronically Epileptic Rats

Abstract

We have shown previously that when postsynaptic NMDA receptors are blocked, the frequency, but not amplitude, of spontaneous EPSCs (sEPSCs) at synapses in the entorhinal cortex is reduced by NMDA receptor antagonists, demonstrating that glutamate release is tonically facilitated by presynaptic NMDA autoreceptors. In the present study, we recorded sEPSCs using whole-cell voltage clamp in neurons in layer V in slices of the rat entorhinal cortex. Using specific antagonists for NR2A [(R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-methyl]-phosphonic acid] and NR2B [(␣R,␤S)-␣-(4-hydroxyphenyl)-␤-methyl-4-(phenylmethyl)-1-piperidinepropanol hydrochloride (Ro 25-6981)] subunit-containing receptors, we confirmed that in slices from juvenile rats (4 -6 weeks of age), the autoreceptor is predominantly of the NR1-NR2B subtype. In older (4 -6 months of age) control animals, the effect of the NR2B antagonist was less marked, suggesting a decline in autoreceptor function with development. In slices from rats (aged 4 -6 months) exhibiting spontaneous recurrent seizures induced with a lithium-pilocarpine protocol, Ro 25-6981 again robustly reduced sEPSC frequency. The effect was equal to or greater than that seen in the juvenile slices and much more pronounced than that seen in the age-matched control animals. In all three groups, the NR2A antagonist was without effect on sEPSCs. These results suggest that there is a developmental decrease in NMDA autoreceptor function, which is reversed in a chronic epileptic condition. The enhanced autoreceptor function may contribute to seizure susceptibility and epileptogenesis in temporal lobe structures.

Synapse-Specific Expression of Functional Presynaptic NMDA Receptors in Rat Somatosensory Cortex

“…PreNMDARs modulate synaptic transmission at many excitatory cortical synapses (Berretta and Jones, 1996;Woodhall et al, 2001;Sjöström et al, 2003;Yang et al, 2006;Corlew et al, 2007), particularly during the first 3 postnatal weeks (Fiszman et al, 2005;Mameli et al, 2005;Corlew et al, 2007). Our results demonstrate that functional, NR2B-containing PreNMDARs are present in L2/3 of S1 at P14 -P22, but are restricted to a specific subset of synapses: they are present at L4 -L2/3 excitatory synapses, but not at other synapses made by L4 cells (L4 -L4 synapses) or at other inputs onto L2/3 cells (synapses of the crosscolumnar L2/3-L2/3 projection).…”

“…Of the four types of NR2 subunits, cortical neurons preferentially express NR2A and/or NR2B (Monyer et al, 1994). In cortex, postsynaptic NMDARs undergo an early postnatal developmental switch from NR2B-containing to NR2A-containing receptors (Monyer et al, 1994;Flint et al, 1997;Kew et al, 1998;Stocca and Vicini, 1998;Tovar and Westbrook, 1999;Liu et al, 2004), whereas PreNMDARs are thought to preferentially retain NR2B subunits (Woodhall et al, 2001;Sjöström et al, 2003;Yang et al, 2006). To determine the subunit composition of PreNMDARs at L4 -L2/3 synapses, we applied the antagonist ifenprodil, which blocks NR2B-containing NMDARs (Williams, 1993).…”

“…Presynaptic NMDARs (PreNMDARs) have been detected physiologically at many cortical synapses, including synapses onto layer 2 (L2) and L5 cells in entorhinal cortex (Berretta and Jones, 1996;Woodhall et al, 2001;Yang et al, 2006), synapses between L5 pyramidal cells in visual cortex (Sjöström et al, 2003), ascending inputs onto L2/3 pyramidal cells (presumptive L4 -L2/3 synapses) in somatosensory cortex (S1) (V. A. , and synapses onto L2/3, L4, and L5 cells in visual cortex (Corlew et al, 2007). Cortical PreNMDARs modulate transmitter release and long-term synaptic depression (LTD) (Sjöström et al, 2003;V.…”

Primary Afferent NMDA Receptors Increase Dorsal Horn Excitation and Mediate Opiate Tolerance in Neonatal Rats

“…Particularly novel in our results is the demonstration that presynaptic rather than postsynaptic NMDARs are involved dynamically in regulating the increased excitation in spinal dorsal horn associated with opiate tolerance. Presynaptic NMDARs increasingly have been implicated in modulating CNS neurotransmission and synaptic plasticity (Duguid and Sjostrom, 2006), including increasing (Duguid and Smart, 2004;Yang et al, 2006) and decreasing (Bardoni et al, 2004) neurotransmitter release. Our findings that high doses of NMDA inhibit mEPSC frequency in superficial spinal laminas replicate the findings of Bardoni et al (2004).…”

In vitro ictogenesis and parahippocampal networks in a rodent model of temporal lobe epilepsy

“…The latter changes along with NMDA receptor upregulation have been reported in pilocarpine-treated parahippocampal areas such as the subiculum (Knopp et al, 2005;de Guzman et al, 2006), the EC (Kobayashi et al, 2003;Kumar and Buckmaster, 2006;Yang et al, 2006;de Guzman et al, 2008) and the lateral amygdala (LA) (Benini and Avoli, 2005). In addition, modified GABA A receptor signaling due to changes in K + /Cl − cotransporter has been identified in the epileptic human subiculum in vitro (Cohen et al, 2002;Wozny et al, 2003;Huberfeld et al, 2007).…”