Long-term potentiation and long-term depression in hippocampal CA1 neurons of mice lacking the IP3 type 1 receptor

Yamagata University, Ямагата, Yamagata, Japan
Neuroscience (Impact Factor: 3.36). 02/2003; 117(4):821-30. DOI: 10.1016/S0306-4522(02)00803-5
Source: PubMed


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.

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    • "Studies of IP 3 R1-null mice (Fujii et al., 2000; Taufiq et al., 2005) and the use of IP 3 R1 antagonists (Fujii et al., 2000; Taufiq et al., 2005) suggest that there is an inverse relationship between IP 3 R1 activity and the magnitude of LTP, consistent with our present observations in the spiny mouse neonate. Increased IP 3 R1 expression may influence LTP by altering AMPA receptor trafficking (Nakata and Nakamura, 2007), and by decreasing calcium influx via NMDA receptors (Nagase et al., 2003). Also, it is possible that the increased IP 3 R1 expression reflects an increase in the size of the endoplasmic reticulum (ER), providing a greater buffering pool into which calcium can be pumped, thus limiting the tetanic stimulus-induced increase in calcium and thereby reducing the magnitude of LTP. "
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    • "As with learning and memory, LTP involves activation of glutamate receptors of the AMPA and NMDA subtypes, and is modulated by acetylcholine acting at muscarinic receptors (Muller et al., 1988; Blitzer et al., 1990; Collingridge, 2003). LTP is mediated by Ca 2+ influx though NMDA receptors and voltage-dependent Ca 2+ channels and is enhanced by acetylcholine-induced Ca 2+ release from IP 3 -sensitive ER stores (Nagase et al., 2003; Malenka and Baer, 2004; Shinoe et al., 2005; Li et al., 2007). Impaired cholinergic signaling is implicated in the early memory loss in AD and, indeed, acetylcholinesterase inhibitors improve cognition in some AD patients (Lleo et al., 2006). "
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    • "It is therefore possible that IP3R-dependent signaling pathways are involved in activity-dependent LTD. However, previous studies have shown that LTD induced by a 1-Hz LFS train in CA1 neurons of IP3R1-lacking mice is not significantly affected (Fujii et al. 2000; Nagase et al. 2003). It is theoretically possible that the above LTD experiments using IP3R1-lacking mice failed to show involvement of IP3Rs in CA1 synaptic plasticity because some other molecular mechanism for LTD induction might have been switched on in the hippocampal CA1 neurons of these mice during development to "
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