During the first week of postnatal life, mossy fibers, the axons of granule cells in the dentate ... more During the first week of postnatal life, mossy fibers, the axons of granule cells in the dentate gyrus, release γ-aminobutyric acid (GABA) which exerts in targets cells a depolarizing action. GABA release is downregulated by presynaptic glutamate and GABA B receptors, activated by ambient glutamate and GABA, respectively. Glutamatergic responses start appearing at the end of the first postnatal week in concomitance with the shift of GABA from the depolarizing to the hyperpolarizing direction. GABAergic signaling is dynamically regulated by activity-dependent processes that play a key role in the refinement of neuronal connectivity and the establishment of the adult neuronal circuit.
Pharmacological properties of 2-amino-4-oxo-5-phosphonopentanoic acid (AOPA) on excitatory amino ... more Pharmacological properties of 2-amino-4-oxo-5-phosphonopentanoic acid (AOPA) on excitatory amino acids mediated responses have been tested in CA1 rat hippocampal neurones, using intracellular recordings and current and voltage clamp techniques. These properties were compared with those of the well-known NMDA antagonist, D(-)2-amino-5-phosphonopentanoic acid (AP-5). AOPA completely abolished the response to NMDA but had no effects on the responses to AMPA, quisqualate and kainate. In voltage clamp experiments AOPA antagonized NMDA-induced currents and produced a parallel shift of the NMDA concentration-response curve. Schild analysis gave a Kd value of 26 microM. AP-5 also produced a similar shift in this curve with a Kd of 6.9 mu.
Intracellular and patch clamp recording techniques were used to investigate the role of GABA in i... more Intracellular and patch clamp recording techniques were used to investigate the role of GABA in immature CA3 hippocampal neurons. During the first postnatal week spontaneous GABA release was detected as spontaneous ongoing synaptic potentials (SPSPs) or giant depolarizing potentials (GDPs). GDPs were generated at regular intervals and regulated by ionotropic glutamate receptors (GluRs), whereas SPSPs occurred randomly and were unaffected by ionotropic GluRs. Both GDPs and SPSPs were positively modulated by metabotropic GluRs through cyclic AMP-dependent protein kinase. Moreover GABA controlled its own release through GABAA and GABAB receptors, probably localized on GABAergic nerve terminals. At this developmental stage, GABA depolarized CA3 pyramidal cells through two distinct classes of chloride-permeable receptors: bicuculline sensitive and insensitive, respectively. The bicuculline-insensitive responses were blocked by picrotoxin in a noncompetitive way. Whole-cell GABA currents, recorded in the presence of bicuculline, had a slower desensitization rate and faster recovery from desensitization. In excised outside-out patches, in the presence of bicuculline, GABA activated single-channel currents with conductances of 14, 22, and 31 pS. These values were similar to those obtained when GABA was applied in the absence of bicuculline. Interestingly, GABA responses obtained in the absence of bicuculline, were sensitive to the blocking effect of zinc, whereas bicuculline-resistant responses were almost unaffected by this divalent cation. Expression of different subunits in native receptors (particularly of the alpha and rho type) may account for the functional differences observed in the present experiments. Activation of bicuculline-insensitive receptors would strengthen and prolong the depolarizing action of GABA, thus favoring the entry of calcium through voltage-dependent calcium channels. This calcium signal may be essential in promoting stabilization of synaptic contacts during a critical period of postnatal development.
Advances in Experimental Medicine and Biology, 1986
The endogenous excitatory amino acids aspartate and glutamate are considered the most likely cand... more The endogenous excitatory amino acids aspartate and glutamate are considered the most likely candidates as putative transmitters in the mammalian CNS. They act on one or more receptors. On the basis of electrophysiological studies, using mainly spinal cord preparations, three classes of excitatory amino acid receptors have been proposed: NMDA, quisqualate and kainate (Watkins and Evans, 1981).
The action of glycine (Gly) intravenously injected on rat epileptic foci induced by strychnine or... more The action of glycine (Gly) intravenously injected on rat epileptic foci induced by strychnine or penicillin topically applied, was compared with that of GABA. Gly (450 mg/kg i.v.) produced a complete block of the spiking activity. The inhibitory action of GABA (80 mg/kg), in terms of threshold and duration, was stronger than the action of Gly. The same inhibitory effect was also observed if these amino acids were applied topically or intracisternally. These results are consistent with the possibility that Gly has a role in the rat cortical inhibition.
Considering that a well-defined dopaminergic projection from the mesencephalic structures to the ... more Considering that a well-defined dopaminergic projection from the mesencephalic structures to the rat frontal cortex has been demonstrated, the purpose of this research was to study the action of iontophoretically applied dopamine (DA) on intracellularly recorded rat frontal neurons. The stimulation of the substantia nigra (SN) and the ventral tegmental area (VTA) evoked EPSP-IPSP sequences in these cells. About 50% of the tested neurons, widely distributed in all the frontal cortex, responded to DA application and no difference in the response to DA was observed between neurons with monosynaptic inputs and neurons with polysynaptic inputs. The catecholamine depolarized the cell membrane and decreased the firing rate, generally without significant changes in membrane resistance, as already observed in rat and cat striatal cells. In some neurons the decrease of the spikes preceded the membrane depolarization. Considering the complex effect of DA on the electrical properties of these neurons, these results seem to be indicative of a mechanism of action dependent on metabolic changes.
During the first week of postnatal life, mossy fibers, the axons of granule cells in the dentate ... more During the first week of postnatal life, mossy fibers, the axons of granule cells in the dentate gyrus, release γ-aminobutyric acid (GABA) which exerts in targets cells a depolarizing action. GABA release is downregulated by presynaptic glutamate and GABA B receptors, activated by ambient glutamate and GABA, respectively. Glutamatergic responses start appearing at the end of the first postnatal week in concomitance with the shift of GABA from the depolarizing to the hyperpolarizing direction. GABAergic signaling is dynamically regulated by activity-dependent processes that play a key role in the refinement of neuronal connectivity and the establishment of the adult neuronal circuit.
Pharmacological properties of 2-amino-4-oxo-5-phosphonopentanoic acid (AOPA) on excitatory amino ... more Pharmacological properties of 2-amino-4-oxo-5-phosphonopentanoic acid (AOPA) on excitatory amino acids mediated responses have been tested in CA1 rat hippocampal neurones, using intracellular recordings and current and voltage clamp techniques. These properties were compared with those of the well-known NMDA antagonist, D(-)2-amino-5-phosphonopentanoic acid (AP-5). AOPA completely abolished the response to NMDA but had no effects on the responses to AMPA, quisqualate and kainate. In voltage clamp experiments AOPA antagonized NMDA-induced currents and produced a parallel shift of the NMDA concentration-response curve. Schild analysis gave a Kd value of 26 microM. AP-5 also produced a similar shift in this curve with a Kd of 6.9 mu.
Intracellular and patch clamp recording techniques were used to investigate the role of GABA in i... more Intracellular and patch clamp recording techniques were used to investigate the role of GABA in immature CA3 hippocampal neurons. During the first postnatal week spontaneous GABA release was detected as spontaneous ongoing synaptic potentials (SPSPs) or giant depolarizing potentials (GDPs). GDPs were generated at regular intervals and regulated by ionotropic glutamate receptors (GluRs), whereas SPSPs occurred randomly and were unaffected by ionotropic GluRs. Both GDPs and SPSPs were positively modulated by metabotropic GluRs through cyclic AMP-dependent protein kinase. Moreover GABA controlled its own release through GABAA and GABAB receptors, probably localized on GABAergic nerve terminals. At this developmental stage, GABA depolarized CA3 pyramidal cells through two distinct classes of chloride-permeable receptors: bicuculline sensitive and insensitive, respectively. The bicuculline-insensitive responses were blocked by picrotoxin in a noncompetitive way. Whole-cell GABA currents, recorded in the presence of bicuculline, had a slower desensitization rate and faster recovery from desensitization. In excised outside-out patches, in the presence of bicuculline, GABA activated single-channel currents with conductances of 14, 22, and 31 pS. These values were similar to those obtained when GABA was applied in the absence of bicuculline. Interestingly, GABA responses obtained in the absence of bicuculline, were sensitive to the blocking effect of zinc, whereas bicuculline-resistant responses were almost unaffected by this divalent cation. Expression of different subunits in native receptors (particularly of the alpha and rho type) may account for the functional differences observed in the present experiments. Activation of bicuculline-insensitive receptors would strengthen and prolong the depolarizing action of GABA, thus favoring the entry of calcium through voltage-dependent calcium channels. This calcium signal may be essential in promoting stabilization of synaptic contacts during a critical period of postnatal development.
Advances in Experimental Medicine and Biology, 1986
The endogenous excitatory amino acids aspartate and glutamate are considered the most likely cand... more The endogenous excitatory amino acids aspartate and glutamate are considered the most likely candidates as putative transmitters in the mammalian CNS. They act on one or more receptors. On the basis of electrophysiological studies, using mainly spinal cord preparations, three classes of excitatory amino acid receptors have been proposed: NMDA, quisqualate and kainate (Watkins and Evans, 1981).
The action of glycine (Gly) intravenously injected on rat epileptic foci induced by strychnine or... more The action of glycine (Gly) intravenously injected on rat epileptic foci induced by strychnine or penicillin topically applied, was compared with that of GABA. Gly (450 mg/kg i.v.) produced a complete block of the spiking activity. The inhibitory action of GABA (80 mg/kg), in terms of threshold and duration, was stronger than the action of Gly. The same inhibitory effect was also observed if these amino acids were applied topically or intracisternally. These results are consistent with the possibility that Gly has a role in the rat cortical inhibition.
Considering that a well-defined dopaminergic projection from the mesencephalic structures to the ... more Considering that a well-defined dopaminergic projection from the mesencephalic structures to the rat frontal cortex has been demonstrated, the purpose of this research was to study the action of iontophoretically applied dopamine (DA) on intracellularly recorded rat frontal neurons. The stimulation of the substantia nigra (SN) and the ventral tegmental area (VTA) evoked EPSP-IPSP sequences in these cells. About 50% of the tested neurons, widely distributed in all the frontal cortex, responded to DA application and no difference in the response to DA was observed between neurons with monosynaptic inputs and neurons with polysynaptic inputs. The catecholamine depolarized the cell membrane and decreased the firing rate, generally without significant changes in membrane resistance, as already observed in rat and cat striatal cells. In some neurons the decrease of the spikes preceded the membrane depolarization. Considering the complex effect of DA on the electrical properties of these neurons, these results seem to be indicative of a mechanism of action dependent on metabolic changes.
Uploads
Papers by A. Cherubini