Long-term potentiation and long-term depression in hippocampal CA1 neurons of mice lacking the IP(3) type 1 receptor.
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.
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ABSTRACT: Exaggerated intracellular Ca(2+) signaling is a robust proximal phenotype observed in cells expressing familial Alzheimer's disease (FAD)-causing mutant presenilins (PSs). The mechanisms that underlie this phenotype are controversial and their in vivo relevance for AD pathogenesis is unknown. Here, we used a genetic approach to identify the mechanisms involved and to evaluate their role in the etiology of AD in two FAD mouse models. Genetic reduction of the type 1 inositol trisphosphate receptor (InsP3R1) by 50% normalized exaggerated Ca(2+) signaling observed in cortical and hippocampal neurons in both animal models. In PS1M146V knock-in mice, reduced InsP3R1 expression restored normal ryanodine receptor and cAMP response element-binding protein (CREB)-dependent gene expression and rescued aberrant hippocampal long-term potentiation (LTP). In 3xTg mice, reduced InsP3R1 expression profoundly attenuated amyloid β accumulation and tau hyperphosphorylation and rescued hippocampal LTP and memory deficits. These results indicate that exaggerated Ca(2+) signaling, which is associated with FAD PS, is mediated by InsP3R and contributes to disease pathogenesis in vivo. Targeting the InsP3 signaling pathway could be considered a potential therapeutic strategy for patients harboring mutations in PS linked to AD.Journal of Neuroscience 05/2014; 34(20):6910-23. · 6.75 Impact Factor
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ABSTRACT: Glutamatergic synapses on pyramidal neurons are formed on dendritic spines where glutamate activates ionotropic receptors, and calcium influx via N-methyl-D-aspartate (NMDA) receptors leads to a localized rise in spine calcium that is critical for the induction of synaptic plasticity. In the basolateral amygdala (BLA), activation of metabotropic receptors is also required for synaptic plasticity, and amygdala-dependent learning. Here using acute brain slices from rats, we show that in BLA principal neurons, high frequency synaptic stimulation activates metabotropic glutamate receptors, and raises spine calcium by releasing calcium from IP3-sensitive calcium stores. This spine calcium release is unevenly distributed, being present in proximal spines, but largely absent in more distal spines. Activation of metabotropic receptors also generated calcium waves that differentially invaded spines as they propagated towards the soma. Dendritic wave invasion was dependent on diffusional coupling between the spine and parent dendrite which was determined by spine neck length; with waves preferentially invading spines with short necks. Spine calcium is a critical trigger for the induction of synaptic plasticity, and our findings suggest that calcium release from IP3-sensitive calcium stores may modulate homosynaptic plasticity through store-release in the spine head, and heterosynaptic plasticity of unstimulated inputs via dendritic calcium wave invasion of the spine head.Journal of Neurophysiology 06/2014; · 3.04 Impact Factor
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ABSTRACT: Significance: Memory is an essential human cognitive function. Consequently, to unravel the cellular and molecular mechanisms responsible for the synaptic plasticity events underlying memory formation, storage and loss represents a major challenge of present day neuroscience. Recent advances: This review article describes first the wide-ranging functions played by intracellular Ca<sup>2+</sup> signals in the activity-dependent synaptic plasticity processes underlying hippocampal spatial memory, to focus next on how the endoplasmic reticulum Ca<sup>2+</sup> release channels, the ryanodine receptors and the inositol 1,4,5-trisphosphate receptors, contribute to these processes. We present a detailed examination of recent evidence supporting the key role played by Ca<sup>2+</sup> release channels in synaptic plasticity, including structural plasticity, and the formation/consolidation of spatial memory in the hippocampus. Critical issues: Changes in cellular oxidative state affect particularly the function of Ca<sup>2+</sup> release channels and alter hippocampal synaptic plasticity and the associated memory processes. Emphasis is placed in this review on how defective Ca<sup>2+</sup> release, presumably due to increased levels of reactive oxygen species, may cause the hippocampal functional defects associated to aging and Alzheimer's disease. Future directions: Additional studies should examine the precise molecular mechanisms whereby Ca<sup>2+</sup> release channels contribute to hippocampal synaptic plasticity and spatial memory formation/consolidation. Future studies should test if redox-modified Ca2+ release channels contribute to generate the intracellular Ca<sup>2+</sup> signals required for sustained synaptic plasticity and hippocampal spatial memory, and whether loss of redox balance and oxidative stress, by altering Ca<sup>2+</sup> release channel function presumably contribute to the abnormal memory processes that occur during aging and Alzheimer's disease.Antioxidants & Redox Signaling 01/2014; · 8.20 Impact Factor