[Show abstract][Hide abstract] ABSTRACT: To investigate the role in synaptic plasticity of Ca(2+) released from intracellular Ca(2+) stores, mice lacking the inositol 1,4,5-trisphosphate type 1 receptor were developed and the physiological properties, long-term potentiation, and long-term depression of their hippocampal CA1 neurons were examined. There were no significant differences in basic synaptic functions, such as membrane properties and the input/output relationship, between homozygote mutant and wild-type mice. Enhanced paired-pulse facilitation at interpulse intervals of less than 60 ms and enhanced post-tetanic potentiation were observed in the mutant mice, suggesting that the presynaptic mechanism was altered by the absence of the inositol 1,4,5-trisphosphate type 1 receptor. Long-term potentiation in the field-excitatory postsynaptic potentials induced by tetanus (100 Hz, 1 s) and the excitatory postsynaptic currents induced by paired stimulation in hippocampal CA1 pyramidal neurons under whole-cell clamp conditions were significantly greater in mutant mice than in wild-type mice. Homosynaptic long-term depression of CA1 synaptic responses induced by low-frequency stimulation (1 Hz, 500 pulses) was not significantly different, but heterosynaptic depression of the non-associated pathway induced by tetanus was blocked in the mutant mice. Both long-term potentiation and long-term depression in mutant mice were completely dependent on N-methyl-D-aspartate receptor activity. To rule out the possibility of an effect compensating for the lack of the inositol 1,4,5-trisphosphate type 1 receptor occurring during development, an anti-inositol 1,4,5-trisphosphate type 1 receptor monoclonal antibody that blocks receptor function was diffused into the wild-type cell through a patch pipette, and the effect of acute block of inositol 1,4,5-trisphosphate type 1 receptor on long-term potentiation was examined. Significant enhancement of long-term potentiation was observed compared with after control immunoglobulin G injection, suggesting that developmental redundancy was not responsible for the increase in long-term potentiation amplitude observed in the mutant mouse. The properties of channels that could be involved in long-term potentiation induction were examined using whole-cell recording. N-methyl-D-aspartate currents were significantly larger in mutant mice than in wild-type mice only between holding potentials of -60 and -80 mV. We conclude that inositol 1,4,5-trisphosphate type 1 receptor activity is not essential for the induction of synaptic plasticity in hippocampal CA1 neurons, but appears to negatively regulate long-term potentiation induction by mild modulation of channel activities.
[Show abstract][Hide abstract] ABSTRACT: Properties of calcium spikes revealed during GABAA receptor antagonism in hippocampal CA1 neurons from guinea pigs. J. Neurophysiol. 78: 2269-2279, 1997. Intracellular electrical responses and changes in intracellular calcium concentration ([Ca2+]i) in response to activation of synaptic inputs and to DC injections were recorded simultaneously from CA1 pyramidal neurons (n = 42) in guinea pig hippocampal slices. In the presence of the gamma-aminobutyric acid-A (GABAA) receptor antagonists, bicuculline (mu M) and picrotoxin (10 mu M, broad (>20 ms) all-or-none spikes were induced by activation of synaptic inputs (20 pulses, 30 Hz) and were accompanied by a simultaneous rapid and large rise in [Ca2+]i (34 of 34 cells). By contrast, direct depolarizing current (0.7 nA, 1 s) induced spikes having short duration, during which time the spike firing pattern was observed not to be significantly affected. When Na+ channels were blocked by QX-314 applied intracellularly through the recording microelectrode in the presence of GABAA receptor antagonists, broad spikes were frequently generated by activation of synaptic inputs (32 of 33 cells). These broad spikes were blocked by Cd2+ (200 mu M) or in Ca2+-free medium (6 of 6 cells) but were resistant to either tetrodotoxin (TTX; 1 micro M; 6 of 6 cells) or QX-314, whereas short-duration spikes were blocked by both TTX and QX-314. Based on these findings we conclude that broad and short-duration spikes are Ca2+ and Na+ spikes, respectively. To investigate the properties of the Ca2+ spikes, antagonists of a voltage-operated Ca2+ channel were applied to the evoked responses. Nifedipine (30 mu M), a L-type Ca2+ channel blocker, suppressed the generation of Ca2+ spikes, whereas Ni2+ (100 mu M), the T- and R-type Ca2+ channel blocker, and omega-agatoxin-IVA (omega-Aga-IVA, 60 nM), a P-type Ca2+ channel blocker, had little effect on the generation of Ca2+ spikes. Nifedipine suppressed the rise in [Ca2+]i induced by synaptic inputs up to 26% of the control in the soma and 18-32% in the dendrites (n = 5), respectively, whereas Ni2+ suppressed the rise by 12-27% (n = 5) in both soma and dendrites. omega-Aga-IVA showed little effect (less than a 10% change; n = 7). These results suggest that the GABAA inhibitory system tonically suppresses dendritic Ca2+ spikes, and the L-type Ca2+ channel plays a major role in the generation of Ca2+ spikes and in Ca2+ influx.
No preview · Article · Nov 1997 · Journal of Neurophysiology
[Show abstract][Hide abstract] ABSTRACT: The effects of both the activation and the blockade of D1 or D2 dopamine receptors on long-term depression (LTD) of synaptic transmission, and the involvement of NMDA and GABA receptors in LTD, were investigated in CA1 neurons of rat hippocampal slices. Low-frequency stimulation (LFS, 450 pulses at 1 Hz) produced LTD of the slope of field EPSPs (-14.3%, mean, n = 10). The induction of LTD was blocked by the NMDA receptor antagonist, AP5 (1.4%, n = 7), by the D1 receptor antagonist, SCH-23390 (3.5%, n = 8), or by the D2 receptor agonist, LY-171555 (4.4%, n = 8). Either the activation of D1 receptors by SKF-38393 or the blockade of D2 receptors by sulpiride produced significantly larger LTD than the control LTD (-31.1%, n = 11; -30.6%, n = 9, respectively). Although LTD was blocked by picrotoxin, a GABAA receptor/Cl- channel antagonist (4.9%, n = 8), LTD was produced by LFS in the medium containing both SKF-38393 and picrotoxin (-27.3%, n = 7). These results indicate that: (1) the induction of LTD by LFS in hippocampal CA1 neurons is under the influence of both NMDA and GABA receptors; (2) both D1 and D2 receptors are involved in the modulation of LTD in that the activation of D1 receptors enhances LTD, while that of D2 receptors inhibits LTD, and (3) while the induction of LTD is blocked by picrotoxin, this effect is superseded by SKF-38393.
No preview · Article · Feb 1996 · Receptors and Channels
[Show abstract][Hide abstract] ABSTRACT: 1. Intracellular recordings, in conjunction with fura-2 fluorescence imaging, were used to evaluate the contribution of the different Ca2+ channel subtypes to the Ca2+ influx induced by back-propagating trains of action potentials. High-threshold channels contributed mainly to Ca2+ influx in pyramidal cell somata and proximal dendrites, whereas low-threshold and other Ni(2+)-sensitive channels played a greater role in more distal dendritic signaling. These data suggest that the different Ca2+ channel types participate in distinct physiological functions; low-threshold channels likely play a greater role in dendritic integration, whereas high-threshold channels are more important for somatic Ca(2+)-dependent processes.
No preview · Article · Jul 1995 · Journal of Neurophysiology