Calcium Currents In Hippocampal Neurons Research Articles

NMDA receptor involvement in antidepressant-like effect of pioglitazone in the forced swimming test in mice

Previously, we showed that pioglitazone exerts its antidepressant-like effect through peroxisome proliferator-activated receptor gamma receptors and demonstrated the possible involvement of calcium-dependent nitric oxide synthase inhibitors. Based upon the in vitro results, pioglitazone reduces N-methyl-D-aspartate (NMDA)-mediated calcium currents in hippocampal neurons. In this study, we evaluated the involvement of the NMDA receptor (NMDAR) on the antidepressant-like effect of pioglitazone in the forced swimming test (FST) in mice. After the assessment of locomotor activity in the open-field test, mice were forced to swim individually and the immobility time of the last 4 min was evaluated. Pioglitazone was administered orally with doses of 5, 10, and 20 mg/kg 4 h before FST. To assess the involvement of NMDARs in the possible antidepressant-like effect of pioglitazone, a selective glutamate receptor agonist, NMDA (75 mg/kg, intraperitoneally [i.p.] or 20 ng/mouse, intracerebroventricularly [i.c.v.]), was administered before pioglitazone (20 mg/kg). To further determine a possible role of NMDARs in this effect, a noncompetitive antagonist of the NMDA, MK-801 (0.05 mg/kg, i.p. or 100 ng/mouse, i.c.v.), was coadministered with pioglitazone (10 mg/kg) 4 h prior to FST. Pioglitazone (20 mg/kg) administered 4 h prior to FST significantly reduced the immobility time. Coadministration of the noneffective doses of pioglitazone and MK-801 revealed an antidepressant-like effect in FST. Moreover, NMDA significantly reversed the antidepressant-like effect of pioglitazone administered 4 h prior to FST. The antidepressant-like effect of pioglitazone in the FST is mediated partly through NMDAR signaling. This study provides a new approach for the treatment of depression.

Isoflurane Inhibits Multiple Voltage-gated Calcium Currents in Hippocampal Pyramidal Neurons

The mechanisms by which volatile anesthetics produce general anesthesia are unknown. Voltage-gated calcium currents in central neurons are potential target sites for general anesthetics because they are involved in the regulation of excitability and are essential for synaptic transmission. Freshly isolated rat hippocampal pyramidal neurons were studied using the whole-cell patch clamp method. Calcium currents were isolated from other voltage-activated currents by blocking sodium and potassium channels. Calcium current subtypes were studied using the specific blockers nitrendipine and omega-conotoxin GVIA. Isoflurane inhibited multiple voltage-gated calcium currents in hippocampal neurons. Isoflurane inhibited both the high- and low-voltage-activated calcium current in a clinically relevant concentration range, giving half-maximal inhibition of the peak high-voltage-activated current (measured at current maximum) at about 2% gas phase concentration, and the sustained current (measured at the end of an 800-ms depolarization) at about 1%. Isoflurane also accelerated both components of the two-component exponential decay of the high-voltage-activated current. Studies using specific channel blockers showed that the calcium current contained contributions from T, L, N, and other channels, including probably P channels. Isoflurane inhibited all of these in clinically relevant concentrations, although detailed analysis of the effects on the individual channel types was not attempted. Given the importance of calcium currents in the regulation of excitability in central neurons and the involvement of P and N channels in neurotransmitter release, this effect may represent an important action of volatile anesthetics in producing general anesthesia.

Quisqualate receptor-mediated depression of calcium currents in hippocampal neurons

The modulation of Ca2+ currents by the excitatory neurotransmitter glutamate and its analogs was investigated in hippocampal neurons in culture. In the presence of glutamate receptor-gated ion channel antagonists, all of the analogs tested caused either a small reversible depression or had no effect on the Ca2+ current. However, in neurons dialyzed with GTP gamma S, quisqualate and glutamate but not NMDA, kainate, AMPA, or L-APB caused marked and irreversible depressions of the Ca2+ current. This inhibition was only observed if Ca2+ was present in either the internal or external medium. Intracellular H-7, staurosporine, IP3, cAMP, cGMP, or calmodulin inhibitors failed to prevent the quisqualate-induced Ca2+ current inhibition. These observations are consistent with an interaction between a G protein-coupled glutamate receptor and Ca2+ channels.

Mild acidosis protects hippocampal neurons from injury induced by oxygen and glucose deprivation

Hippocampal neurons are extremely sensitive to ischemic injury; two plausible mechanisms have been implicated in mediating such damage. The first involves overexposure of neurons to excitatoryN-methyl- d-aspartate (NMDA) receptor agonists, which mobilize damaging concentrations of intracellular calcium; the second involves the generation of damaging tissue acidosis. A recent report shows that exposure to pH 6.6 can block NMDA-induced calcium currents in hippocampal neurons. This suggests that moderate acidity might protect against NMDA-mediated neurotoxicity and ischemic injury in vivo. We have observed such projection in vitro using primary hippocampal cultures. At an extracellular pH of 7.4, 6 h of glucose-free anoxia caused delayed and profound damage to neurons which was partially attenuated by the NMDA receptor antagonist, 2-amino-5-phosphonovaleric acid (APV). Dropping the pH to 6.5 provided virtually complete protection against this insult. Thus, acidosis need not be viewed exclusively as a damaging component of ischemic insults.