6-cyano-7-nitroquinoxaline-2-3-dione and 4-diphenylacetoxy-1-1-dimethylpiperidinium

Spontaneous waves of excitation in the developing mammalian retina are mediated, to a large extent, by neurotransmission. However, it is unclear how the underlying neurotransmitter systems interact with each other to play specific roles in the formation of retinal waves at various developmental stages. In particular, it is puzzling why the waves maintain a similar propagation pattern even after underlying neurotransmitter systems have undergone drastic developmental changes. Using Ca(2+) imaging and patch clamp in a whole-mount preparation of the developing rabbit retina, we discovered two dramatic and coordinated transitions in the excitatory drive for retinal waves: one from a nicotinic to a muscarinic system, and the other from a fast cholinergic to a fast glutamatergic input. Retinal waves before the age of postnatal day 1 (P1) were blocked by nicotinic antagonists, but not by muscarinic or glutamatergic antagonists. After P3, however, the spontaneous wave, whose basic spatiotemporal pattern remained similar, was completely inhibited by muscarinic or glutamate antagonists, but not by nicotinic antagonists. We also found that the muscarinic drive, mediated primarily by M1 and M3 receptors, was particularly important for wave propagation, whereas the glutamatergic drive seemed more important for local excitation. Our results suggest (1) a novel mechanism by which a neurotransmitter system changes its functional role via a switch between two completely different classes of receptors for the same transmitter, (2) the cholinergic system plays a critical role in not only early but also late spontaneous waves, and (3) the continued participation of the cholinergic system may provide a network basis for the consistency in the overall propagation pattern of spontaneous retinal waves.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Aging; Animals; Animals, Newborn; Atropine; Bungarotoxins; Calcium; Curare; Dimethylphenylpiperazinium Iodide; Excitatory Amino Acid Antagonists; Fluorescent Dyes; Fura-2; Hexamethonium; Membrane Potentials; Muscarine; Muscarinic Antagonists; Neurotransmitter Agents; Nicotinic Antagonists; Patch-Clamp Techniques; Piperidines; Rabbits; Retina; Retinal Ganglion Cells

The aim of this study was to characterize the modulation of synaptic transmission in the glutamatergic corticostriatal pathway by cholinergic and adrenergic receptors. In coronal slices of mouse brain, negative-going field potentials were recorded in the dorsal striatum in response to stimulation of the overlying white matter, and their susceptibility to various pharmacological manipulations was studied. The responses were mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors, since they were augmented by aniracetam (0.5-1.5 mM), a positive modulator of AMPA-type glutamate receptors, and blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (> or = 10 microM), a selective antagonist of AMPA receptors. Carbachol (10 microM), a muscarinic agonist, reduced the size of responses and abolished paired-pulse depression; these effects being consistent with previous studies indicating that muscarinic activation inhibits release of glutamate in the corticostriatal pathway. Muscarinic antagonists could block the effect of carbachol. Their rank order was: 10 microM scopolamine (a non-selective muscarinic antagonist) > or = 1 microM 4-diphenylacetoxy-N-methyl-piperidine (M3/M1 antagonist)>1 microM pirenzepine (M1 antagonist)>10 microM methoctramine (M2 antagonist). McN-A-343 (1-10 microM), an M1 muscarinic agonist, was ineffective in this preparation. In contrast, isoproterenol (10-30 microM), a beta-adrenergic agonist, slightly increased the synaptic responses, but it did not affect paired-pulse depression. None of alpha-adrenergic agents (30 nM-1.0 microM dexmedetomidine, an alpha2-adrenergic agonist, 0.3 microM atipamezole, an alpha2-adrenergic antagonist or 30 microM phenylephrine, an alpha1-adrenergic agonist) influenced the size of the responses; neither did these drugs alter paired-pulse depression. These results indicate that the activation of striatal M3-like muscarinic receptors and beta-adrenoceptors, but not M2-like muscarinic receptors and alpha-adrenoceptors, modulates directly corticostriatal glutamatergic neurotransmission.

Topics: (4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; 6-Cyano-7-nitroquinoxaline-2,3-dione; Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Adrenergic beta-Agonists; Adrenergic Fibers; Animals; Carbachol; Cerebral Cortex; Cholinergic Fibers; Corpus Striatum; Diamines; Excitatory Amino Acid Agonists; Excitatory Postsynaptic Potentials; Glutamic Acid; Imidazoles; Isoproterenol; Male; Medetomidine; Mice; Mice, Inbred DBA; Muscarinic Agonists; Muscarinic Antagonists; Phenylephrine; Piperidines; Pirenzepine; Pyrrolidinones; Receptor, Muscarinic M2; Receptor, Muscarinic M3; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Receptors, AMPA; Receptors, Muscarinic; Scopolamine; Synaptic Transmission