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: The role of the cyclic nucleotide-gated (CNG) channel CNGA3 is well established in cone photoreceptors and guanylyl cyclase-D-expressing olfactory neurons. To assess a potential function of CNGA3 in the mouse amygdala and hippocampus, we examined synaptic plasticity and performed a comparative analysis of spatial learning, fear conditioning and step-down avoidance in wild-type mice and CNGA3 null mutants (CNGA3(-/-) ). CNGA3(-/-) mice showed normal basal synaptic transmission in the amygdala and the hippocampus. However, cornu Ammonis (CA1) hippocampal long-term potentiation (LTP) induced by a strong tetanus was significantly enhanced in CNGA3(-/-) mice as compared with their wild-type littermates. Unlike in the hippocampus, LTP was not significantly altered in the amygdala of CNGA3(-/-) mice. Enhanced hippocampal LTP did not coincide with changes in hippocampus-dependent learning, as both wild-type and mutant mice showed a similar performance in water maze tasks and contextual fear conditioning, except for a trend toward higher step-down latencies in a passive avoidance task. In contrast, CNGA3(-/-) mice showed markedly reduced freezing to the conditioned tone in the amygdala-dependent cued fear conditioning task. In conclusion, our study adds a new entry on the list of physiological functions of the CNGA3 channel. Despite the dissociation between physiological and behavioral parameters, our data describe a so far unrecognized role of CNGA3 in modulation of hippocampal plasticity and amygdala-dependent fear memory.Genes Brain and Behavior 03/2011; 10(2):137-48. · 3.60 Impact Factor
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ABSTRACT: Fragile X syndrome is a leading heritable cause of mental retardation that results from the loss of FMR1 gene function. A Drosophila model for Fragile X syndrome, based on the loss of dfmr1 activity, exhibits phenotypes that bear similarity to Fragile X-related symptoms. Herein, we demonstrate that treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium can rescue courtship and mushroom body defects observed in these flies. Furthermore, we demonstrate that dfmr1 mutants display cognitive deficits in experience-dependent modification of courtship behavior, and treatment with mGluR antagonists or lithium restores these memory defects. These findings implicate enhanced mGluR signaling as the underlying cause of the cognitive, as well as some of the behavioral and neuronal, phenotypes observed in the Drosophila Fragile X model. They also raise the possibility that compounds having similar effects on metabotropic glutamate receptors may ameliorate cognitive and behavioral defects observed in Fragile X patients.Neuron 04/2005; 45(5):753-64. · 15.77 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