Depression of glutamatergic and GABAergic synaptic responses in striatal spiny neurons by stimulation of presynaptic GABAB receptors.
The influence of gamma-aminobutyric acidB (GABAB) receptor stimulation on the excitatory and inhibitory synaptic potentials and membrane properties of identified striatal spiny neurons was examined in a corticostriatal slice preparation. Stimulation of the subcortical white matter evoked a monosynaptic, excitatory postsynaptic potential (EPSP) and a polysynaptic, inhibitory postsynaptic potential (IPSP) in spiny neurons. The EPSP had two components: a large amplitude response which could be blocked by the kainate/quisqualate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM), and a small amplitude, long-duration depolarization which could be blocked by the N-methyl-D-aspartate receptor antagonist, d-(-)-2-amino-5-phosphonovaleric acid (APV, 100 microM). The IPSP was observed as a membrane depolarization when recorded from neurons at resting membrane potential. However, when neurons were injected with the Na(+)-channel blocker, QX-314, allowing cells to be depolarized above their spike thresholds, a prominent hyperpolarizing IPSP was readily observed which could be blocked by the GABAA antagonist, bicuculline (10-50 microM). This bicuculline-sensitive IPSP was responsible for the inhibition of EPSP amplitude and probability of spike discharge revealed using paired stimulation of the subcortical white matter. The amplitude of both the EPSP and the IPSP were depressed by the GABAB receptor agonist, p-chlophenyl-GABA (baclofen, 0.5-100 microM) in a concentration-dependent manner. Baclofen also blocked paired stimulus inhibition of spike discharge. These effects of baclofen persisted in slices in which the cortex was removed and were reversed by the GABAB receptor antagonist, 3-amino-3-hydroxy-2-(4-chlorophenyl)-propanesulphonic acid (saclofen, 100-500 microM). In contrast to its profound influence on synaptic input, baclofen did not alter resting membrane potential, input resistance, membrane current-voltage relationship, or spike threshold of the cells recorded, and therefore did not appear to exert direct postsynaptic effects on the striatal spiny neurons. Taken together, these data indicate that the depressant effects of baclofen on EPSPs are mediated through GABAB receptors located on the terminals of glutamatergic afferents within the striatum. Moreover, the results suggest that the actions of baclofen on IPSPs and paired stimulus inhibition are produced by activation of GABAB receptors within the striatum at a site presynaptic to spiny neurons, either on the terminals of GABAergic afferents or on an interposed non-spiny GABAergic cell. Thus, GABAB hetero- and auto-receptors have the capacity to provide a negative feedback mechanism through which the major excitatory and inhibitory inputs to striatal spiny neurons are regulated.
Nisenbaum
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Department of Behavioral Neuroscience, University of Pittsburgh, Pennsylvania 15260.
Berger
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Grace
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D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology*; D004558:Electric Stimulation; D005071:Evoked Potentials / Q000187:drug effects; D005971:Glutamates / Q000502:physiology*; D018698:Glutamic Acid; D066298:In Vitro Techniques; D008012:Lidocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011280:Pregnanolone / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000187:drug effects / Q000502:physiology*; D026941:Sodium Channel Blockers; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D005971:Glutamates; D011810:Quinoxalines; D018080:Receptors, GABA-B; D026941:Sodium Channel Blockers; C012647:QX-314; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015763:2-Amino-5-phosphonovalerate; D008012:Lidocaine; D011280:Pregnanolone; D001418:Baclofen; D001640:Bicuculline