Regulation of excitatory input to inhibitory interneurons of the dentate gyrus during hypoxia.
The role of metabotropic glutamate receptors (mGluRs) and adenosine receptors in hypoxia-induced suppression of excitatory synaptic input to interneurons residing at the granule cell-hilus border in the dentate gyrus was investigated with the use of whole cell electrophysiological recording techniques in thin (250 microns) slices of immature rat hippocampus. Minimal stimulation evoked glutamatergic excitatory postsynaptic currents (EPSCs) in dentate interneurons in 68 +/- 4% (mean +/- SE) of trials during stimulation in the dentate granule cell layer (GCL) and 48 +/- 3% of trials during stimulation in CA3. Hypoxic episodes, produced by switching the perfusing solution from 95% O2-5% CO2 to a solution containing 95% N2-5% CO2 for 3-5 min, rapidly and reversibly decreased the synaptic reliability, or probability of evoking an EPSC, from either input without reducing EPSC amplitude, consistent with a presynaptic suppression of transmitter release. The mGluR antagonist (+)-alpha-methyl-4-carboxyphenylglycine [(+) MCPG; 500 microM] did not alter synaptic reliability or mean EPSC amplitude in either pathway. However, (+) MCPG significantly attenuated hypoxic suppression of input from both pathways, suggesting that mGluRs activated by release of glutamate partially mediate hypoxic suppression of EPSCs to dentate interneurons. The mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD; 100 microM) rapidly decreased the reliability of excitatory transmission from both the GCL (19 +/- 5% of control) and CA3 (39 +/- 15% of control). ACPD also increased the frequency of spontaneous EPSCs and evoked a slow inward current in dentate interneurons. Exogenous adenosine (10-300 microM) decreased synaptic reliability for both pathways and reduced the frequency of spontaneous EPSCs, but did not cause a decrease in the mean amplitude of evoked EPSCs, consistent with a presynaptic suppression of excitatory input to dentate interneurons. Conversely, the selective adenosine A1 receptor antagonists 8-cyclopentyl-1,3-dipropylxanthine (200 nM to 1 microM) and N6-cyclopentyl-9-methyladenine (1 microM) enhanced excitatory input to dentate interneurons by increasing synaptic reliability for both the GCL and CA3 inputs. Adenosine A1 receptor antagonists did not, however, reduce hypoxic suppression of excitatory input to dentate interneurons. These results indicate that hypoxia induces a presynaptic inhibition of excitatory input to dentate interneurons mediated in part by activation of mGluRs, but not adenosine A1 receptors, whereas both mGluRs and adenosine A1 receptors can depress excitatory input to dentate interneurons during normoxic stimulation. Regulation of excitatory input to dentate interneurons provides a mechanism to shape excitatory input to the hippocampus under both normal and pathological conditions.
Doherty
J
J
Department of Pharmacology, Emory University Medical School, Atlanta, Georgia 30322, USA.
Dingledine
R
R
D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D018891:Dentate Gyrus / Q000473:pathology / Q000503:physiopathology*; D004594:Electrophysiology; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D002534:Hypoxia, Brain / Q000473:pathology / Q000503:physiopathology*; D066298:In Vitro Techniques; D007395:Interneurons / Q000502:physiology*; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000502:physiology; D018047:Receptors, Purinergic P1 / Q000187:drug effects; D009435:Synaptic Transmission / Q000502:physiology
D001565:Benzoates; D018691:Excitatory Amino Acid Antagonists; D058915:Purinergic P1 Receptor Antagonists; D018094:Receptors, Metabotropic Glutamate; D018047:Receptors, Purinergic P1; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; C079694:alpha-methyl-4-carboxyphenylglycine; D005998:Glycine