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.
"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. "
[Show abstract][Hide abstract] ABSTRACT: Clinically, treatment options where fetal distress is anticipated or identified are limited. Allopregnanolone is an endogenous steroid, that positively modulates the GABA(A) receptor, and that has anti-apoptotic and anti-excitotoxic actions, reducing brain damage in adult animal models of brain injury. We sought to determine if prophylactic treatment of the pregnant female with a single dose of this steroid could reduce birth asphyxia-induced losses in hippocampal function at 5 days of age (P5) in spiny mouse neonates (Acomys cahirinus). At 37 days gestation (term=39 days) and 1h before inducing birth asphyxia, spiny mice dams were injected subcutaneously (0.2 ml) with either 3mg/kg allopregnanolone or 20% w/v β-cyclodextrin vehicle. One hour later, fetuses were either delivered immediately by caesarean section (control group) or exposed to 7.5 min of in utero asphyxia, causing acidosis and hypoxia. At P5, ex vivo hippocampal plasticity was assessed, or brains collected to determine cell proliferation (proliferating cell nuclear antigen; PCNA) or calcium channel expression (inositol trisphosphate receptor type 1; IP(3)R1) using immunohistochemistry. Allopregnanolone partially prevented the decrease in long term potentiation at P5, and the asphyxia-induced increase in IP(3)R1 expression in CA1 pyramidal neurons. There was no effect of allopregnanolone on the asphyxia induced impairment of the input/output (I/O) curve and paired-pulse facilitation (PPF). In control birth pups, maternal allopregnanolone treatment caused significant changes in short term post-synaptic plasticity and also reduced hippocampal proliferation at P5. These findings show that allopregnanolone can modulate hippocampal development and synaptic function in a normoxic or hypoxic environment, possibly by modifying calcium metabolism. Best practice for treatment dose and timing of treatment will need to be carefully considered.
Brain research 11/2011; 1433:9-19. DOI:10.1016/j.brainres.2011.11.035 · 2.84 Impact Factor
"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). "
[Show abstract][Hide abstract] ABSTRACT: Presenilin-1 (PS1) mutations cause many cases of early-onset inherited Alzheimer's disease, in part, by increasing the production of neurotoxic forms of amyloid beta-peptide (Abeta). However, Abeta-independent effects of mutant PS1 on neuronal Ca(2+) homeostasis and sensitivity to excitatory neurotransmitters have been reported. Here we show that cholinergic modulation of hippocampal synaptic plasticity is impaired in PS1 mutant knockin (PS1KI) mice. Whereas activation of muscarinic receptors enhances LTP at CA1 synapses of normal mice, it impairs LTP in PS1KI mice. Similarly, mutant PS1 impairs the ability of the cholinesterase inhibitor phenserine to enhance LTP. The NMDA current is decreased in CA1 neurons of PS1KI mice and is restored by intracellular Ca(2+)chelation. Similar alterations in acetylcholine and NMDA receptor-mediated components of synaptic plasticity are evident in 3xTgAD mice with PS1, amyloid precursor protein and tau mutations, suggesting that the adverse effects of mutant PS1 on synaptic plasticity can occur in the absence or presence of amyloid and tau pathologies.
Neurobiology of aging 11/2008; 30(7):1061-8. DOI:10.1016/j.neurobiolaging.2007.10.009 · 5.01 Impact Factor
"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 "
[Show abstract][Hide abstract] ABSTRACT: The role of inositol 1, 4, 5-trisphosphate receptors (IP3Rs) in long-term potentiation (LTP) and long-term depression (LTD) was studied in CA1 neurons in guinea pig hippocampal slices. In standard solution, short tetanic stimulation consisting of 15 pulses at 100 Hz induced LTP, while three short trains of low-frequency stimulation (LFS; 200 pulses at 1 Hz) at 18-min intervals or one long train of LFS (1000 pulses at 1 Hz) induced stable LTD in both the slope of the field EPSP (S-EPSP) and the amplitude of the population spike (A-PS). Bath application of 2-aminoethoxydiphenyl borate (2-APB), an IP3R antagonist, or of alpha-methyl-4-carboxyphenylglycine (MCPG), a wide-spectrum metabotropic glutamate receptor antagonist, during weak tetanic stimulation significantly increased the magnitude of the LTP in both the S-EPSP and A-PS. Three short trains of LFS or one long train of LFS delivered in the presence of 2-APB or MCPG did not induce LTD, but elicited LTP. Based on these results, we conclude that, in hippocampal CA1 neurons, IP3Rs play an important role in synaptic plasticity by attenuating LTP and facilitating LTD.
Marion Kuhn, Florian Mainberger, Bernd Feige, Jonathan G Maier, Volker Mall, Nicolai H Jung, Janine Reis, Stefan Klöppel, Claus Normann, Christoph Nissen
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