strychnine and 3-4-dihydroxyphenylglycol

Oligodendrocyte precursor cells (OPCs), a major glial cell type that gives rise to myelinating oligodendrocytes in the CNS, express calcium-permeable AMPA receptors (CP-AMPARs). Although CP-AMPARs are important for OPC proliferation and neuron-glia signaling, they render OPCs susceptible to ischemic damage in early development. We identified factors controlling the dynamic regulation of AMPAR subtypes in OPCs from rat optic nerve and mouse cerebellar cortex. We found that activation of group 1 mGluRs drove an increase in the proportion of CP-AMPARs, reflected by an increase in single-channel conductance and inward rectification. This plasticity required the elevation of intracellular calcium and used PI3K, PICK-1 and the JNK pathway. In white matter, neurons and astrocytes release both ATP and glutamate. Unexpectedly, activation of purinergic receptors in OPCs decreased CP-AMPAR expression, suggesting a capacity for homeostatic regulation. Finally, we found that stargazin-related transmembrane AMPAR regulatory proteins, which are critical for AMPAR surface expression in neurons, regulate CP-AMPAR plasticity in OPCs.

Topics: Animals; Animals, Newborn; Antigens; Biophysical Phenomena; Calcium; Calcium Channels; Carrier Proteins; Cell Cycle Proteins; Cell Differentiation; Cell Lineage; Cerebellum; Enzyme Inhibitors; Excitatory Amino Acid Agents; Female; Galactosylceramidase; Gene Expression Regulation, Developmental; Glutamic Acid; Glycine Agents; In Vitro Techniques; Ion Channel Gating; Luminescent Proteins; Male; Membrane Potentials; Methoxyhydroxyphenylglycol; Mice; Mice, Transgenic; Mutation; Neuronal Plasticity; Nuclear Proteins; Oligodendroglia; Optic Nerve; Proteoglycans; Rats; Receptors, AMPA; Signal Transduction; Stem Cells; Strychnine; Tetrodotoxin

While group I glutamate metabotropic (mGlu) receptors show discrete neuronal distribution in the neonatal rat spinal cord, the functional role of their distinct receptor subtypes remains uncertain. Intracellular recording from lumbar motoneurons together with extracellular recording of ventral root (VR) responses was used to investigate the differential contribution by mGlu receptor subtypes to cell excitability and network activity. The group I agonist DHPG evoked motoneuron depolarization (via the AIDA or CPCCOEt-sensitive mGlu receptor subtype 1) mainly at network level and generated sustained, network-dependent oscillations (via the MPEP-sensitive mGlu receptor subtype 5). DHPG also decreased the peak amplitude of synaptic responses induced by dorsal root stimuli, an effect unrelated to depolarization and dependent on glycinergic transmission. Synaptic responses were insensitive to AIDA or MPEP. The present results can be explained by assuming excitation of discrete classes of interneurons by group I mGlu receptor activity. Thus, the cellular distribution of those mGlu receptors at strategic circuit connections may determine the functional outcome of the network in terms of excitation or inhibition. Even if there was insufficient activation by endogenous glutamate of mGlu receptors during synaptic activity evoked by DR stimuli, it is apparent that such receptors are important pharmacological targets for powerful and rapid up- or down-regulation of spinal signal processing at network level, providing a rationale for the proposed use of mGlu receptor agonists in a variety of spinal pathological conditions.

Topics: Animals; Animals, Newborn; Bicuculline; Drug Interactions; Electric Stimulation; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; GABA Antagonists; Glycine Agents; In Vitro Techniques; Membrane Potentials; Methoxyhydroxyphenylglycol; Motor Neurons; Neural Inhibition; Rats; Receptors, Metabotropic Glutamate; Spinal Cord; Strychnine; Time Factors

The effects of group I metabotropic glutamate (mGlu) receptors on excitatory transmission in the rat dorsal horn, but mostly substantia gelatinosa, neurons were investigated using conventional intracellular recording in slices. The broad spectrum mGlu receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S, 3R-ACPD), the group I mGlu receptor selective agonist (S)-3, 5-dihydroxyphenylglycine (DHPG), and the selective mGlu subtype 5 agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), all induce long-lasting depression of A primary afferent fibers-mediated monosynaptic excitatory postsynaptic potential (EPSP), and long-lasting potentiation of polysynaptic EPSP, and EPSP in cells receiving C-afferent fiber input. The DHPG potentiation of polysynaptic EPSP was partially or fully reversed by (S)-4-carboxyphenylglycine (S-4CPG), the mGlu subtype 1 preferring antagonist. 2-Methyl-6-(phenylethynyl)-pyridine, the potent and selective mGlu subtype 5 antagonist, partially reversed the CHPG potentiation of polysynaptic EPSP. The effects of DHPG on monosynaptic and polysynaptic EPSPs were reduced, or abolished, by the N-methyl-D-aspartate (NMDA) receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (AP5). A clear and pronounced facilitation of the expression of DHPG- and CHPG-induced enhancement of polysynaptic EPSP, and EPSP evoked at C-fiber strength, was seen in the absence of gamma-aminobutyric acid subtype A receptor- and glycine-mediated synaptic inhibition. Besides dual modulation of excitatory synaptic transmission, DHPG induces depression of inhibitory postsynaptic potentials evoked by primary afferent stimulation in dorsal horn neurons. In addition, group I mGlu receptor agonists produced a direct persistent excitatory postsynaptic effect consisting of a slow membrane depolarization, an increase in input resistance, and an intense neuronal discharge. Cyclothiazide and (S)-4-CPG, the mGlu receptor subtype 1 preferring antagonists, significantly attenuated the DHPG-induced depolarization. These results demonstrate that the pharmacological activation of group I metabotropic glutamate receptors induces long-term depression (LTD) and long-term potentiation (LTP) of synaptic transmission in the spinal dorsal horn. These types of long-term synaptic plasticity may play a functional role in the generation of post-injury hypersensitivity (LTP) or antinociception (LTD).

Topics: Animals; Benzoates; Bicuculline; Cycloleucine; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Female; Glycine; In Vitro Techniques; Kinetics; Magnesium; Male; Methoxyhydroxyphenylglycol; Nerve Fibers; Phenylacetates; Posterior Horn Cells; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Spinal Cord; Strychnine; Substantia Gelatinosa; Synaptic Transmission