bicuculline-methobromide and 2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline

Epileptiform discharges recorded in the 4-aminopyridine (4-AP) in vitro epilepsy model are mediated by glutamatergic and GABAergic signaling. Using a 60-channel perforated multi-electrode array (pMEA) on corticohippocampal slices from 2 to 3 week old mice we recorded interictal- and ictal-like events. When glutamatergic transmission was blocked, interictal-like events no longer initiated in the hilus or CA3/CA1 pyramidal layers but originated from the dentate gyrus granule and molecular layers. Furthermore, frequencies of interictal-like events were reduced and durations were increased in these regions while cortical discharges were completely blocked. Following GABA(A) receptor blockade interictal-like events no longer propagated to the dentate gyrus while their frequency in CA3 increased; in addition, ictal-like cortical events became shorter while increasing in frequency. Lastly, drugs that affect tonic and synaptic GABAergic conductance modulated the frequency, duration, initiation and propagation of interictal-like events. These findings confirm and expand on previous studies indicating that multiple synaptic mechanisms contribute to synchronize neuronal network activity in forebrain structures. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.

Topics: 4-Aminopyridine; Animals; Anticonvulsants; Bicuculline; CA3 Region, Hippocampal; Disease Models, Animal; Electrodes; Epilepsy; GABA-A Receptor Antagonists; gamma-Aminobutyric Acid; Hippocampus; In Vitro Techniques; Isoxazoles; Mice; Mice, Inbred C57BL; Microarray Analysis; Motion Pictures; Piperazines; Potassium Channel Blockers; Quinoxalines; Receptors, N-Methyl-D-Aspartate; Software; Somatosensory Cortex

Although rare, interneurons are pivotal in governing striatal output by extensive axonal arborizations synapsing on medium spiny neurons. Using a genetically modified mouse strain in which a green fluorescent protein (GFP) is driven to be expressed under control of the neuropeptide Y (NPY) promoter, we identified NPY interneurons and compared them with striatal principal neurons. We found that the bacteria artificial chromosome (BAC)-npy mouse expresses GFP with high fidelity in the striatum to the endogenous expression of NPY. Patch-clamp analysis from NPY neurons showed a heterogeneous population of striatal interneurons. In the majority of cells, we observed spontaneous firing of action potentials in extracellular recordings. On membrane rupture, most NPY interneurons could be classified as low-threshold spiking interneurons and had high-input resistance. Voltage-clamp recordings showed that both GABA and glutamate gated ion channels mediate synaptic inputs onto these striatal interneurons. AMPA receptor-mediated spontaneous excitatory postsynaptic currents (sEPSCs) were small in amplitude and infrequent in NPY neurons. Evoked EPSCs did not show short-term plasticity but some rectification. Evoked N-methyl-d-aspartate (NMDA) EPSCs had fast decay kinetics and were poorly sensitive to an NR2B subunit containing NMDA receptor blocker. Spontaneous inhibitory postsynaptic currents (sIPSCs) were mediated by GABA(A) receptors and were quite similar among all striatal neurons studied. On the contrary, evoked IPSCs decayed faster in NPY neurons than in other striatal neurons. These data report for the first time specific properties of synaptic transmission to NPY striatal interneurons.

Topics: Animals; Bicuculline; Biophysical Phenomena; Biophysics; Choline O-Acetyltransferase; Corpus Striatum; Electric Stimulation; Excitatory Amino Acid Antagonists; GABA Antagonists; Green Fluorescent Proteins; Interneurons; Mice; Mice, Transgenic; Neural Inhibition; Neuropeptide Y; Organophosphonates; Parvalbumins; Patch-Clamp Techniques; Piperazines; Quinoxalines; Sodium Channel Blockers; Synapses; Synaptic Potentials; Tetrodotoxin

GABA uptake limits GABA actions during synaptic responses when the density of active release sites is high or multiple axons are synchronously activated. GABA transporter-1 (GAT-1) is the main neuronal GABA transporter subtype and is already expressed in the early postnatal rat hippocampus. However, previous studies have demonstrated little functional role for the transporter during this developmental period. We used whole-cell voltage-clamp and field-potential recordings in hippocampal slices of neonatal rats (postnatal day 4-5) to study whether GAT-1 plays a role in GABAergic transmission during spontaneous population oscillations, which are seen as "giant depolarizing potentials" (GDPs) in intracellular recordings. We show that the GDP-associated GABAergic current observed in CA3 pyramidal neurons is strongly enhanced by the GAT-1-specific blocker NO-711 (1-[2-[[(diphenylmethylene)imino]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride). Our results indicate a novel role for GAT-1 in the control of endogenous activity of the immature hippocampus.

Topics: Animals; Animals, Newborn; Bicuculline; GABA Antagonists; GABA Plasma Membrane Transport Proteins; gamma-Aminobutyric Acid; Hippocampus; Interneurons; Membrane Transport Proteins; Neurotransmitter Uptake Inhibitors; Nipecotic Acids; Oximes; Patch-Clamp Techniques; Pyramidal Cells; Quinoxalines; Rats; Rats, Wistar; Synaptic Transmission; Tetrodotoxin