Fast network oscillations in the hippocampal CA1 region of the behaving rat.
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This study examined intermittent, high-frequency (100-200 Hz) oscillatory patterns in the CA1 region of the hippocampus in the absence of theta activity, i.e., during and in between sharp wave (SPW) bursts. Pyramidal and interneuronal activity was phase-locked not only to large amplitude (>7 SD from baseline) oscillatory events, which are present mainly during SPWs, but to smaller amplitude (<4 SD) patterns, as well. Large-amplitude events were in the 140-200 Hz, "ripple" frequency range. Lower-amplitude events, however, contained slower, 100-130 Hz ("slow") oscillatory patterns. Fast ripple waves reversed just below the CA1 pyramidal layer, whereas slow oscillatory potentials reversed in the stratum radiatum and/or in the stratum oriens. Parallel CA1-CA3 recordings revealed correlated CA3 field and unit activity to the slow CA1 waves but not to fast ripple waves. These findings suggest that fast ripples emerge in the CA1 region, whereas slow (100-130 Hz) oscillatory patterns are generated in the CA3 region and transferred to the CA1 field. (+info)
Requirements for LTP induction by pairing in hippocampal CA1 pyramidal cells.
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The induction of long-term potentiation (LTP) in the hippocampal CA1 region requires both presynaptic activity and large postsynaptic depolarization. A standard protocol for inducing LTP using whole-cell recording is to pair low-frequency synaptic stimulation (100-200 pulses, 1-2 Hz) with a depolarizing voltage-clamp pulse (1-3 min duration). In this standard protocol, a Cs(+)-based internal solution is used to improve the fidelity of the depolarization produced by voltage-clamp. In an attempt to induce LTP more rapidly, we tried to induce LTP by pairing high-frequency stimulation (200 pulses, 20-100 Hz) with a short depolarization ( approximately 15 s). Surprisingly, we found that this protocol failed to induce LTP, even though large LTP ( approximately 300% of baseline) could be induced by a subsequent standard protocol in the same cell. Pairing brief high-frequency stimulation at the beginning of a long depolarization (3 min) also did not induce LTP. However, the same high-frequency stimulation at the end of the long depolarization did induce LTP. When similar experiments were done with a K(+)-based internal solution, pairing high-frequency stimulation with a short depolarization did induce LTP. This indicates that the requirement for long depolarization is related to the use of Cs(+). We speculate that, when recording is made with Cs(+), a tetanus given at the beginning of depolarization initiates a process that inhibits N-methyl-D-aspartate (NMDA)-dependent LTP. This inhibitory process itself decays away during prolonged depolarization. (+info)
Cl- accumulation does not account for the depolarizing phase of the synaptic GABA response in hippocampal pyramidal cells.
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It has been proposed that the depolarizing phase of the biphasic synaptic GABA response could be mediated by HCO3- passing through GABA(A) channels after dissipation of the transmembrane Cl- gradient due to intracellular Cl- accumulation. To test this hypothesis, giant GABA-mediated postsynaptic currents (GPSCs) were recorded from pyramidal cells in slices of adult guinea pig hippocampus in the presence of 4-aminopyridine. GPSCs consisted of an early outward current (GABA(A) component) followed by a late inward current (GABA(D) component). Spontaneous outward inhibitory postsynaptic currents (IPSCs) occurred during the GABA(D) component of the GPSC. GPSCs that were evoked 1-12 s after the preceding GPSC (short interval, siGPSCs) showed no GABA(D) component even though in many cells the amplitude of the siGPSC was greater than the amplitude of the GABA(A) component of the preceding spontaneous GPSC. In addition, the siGPSC evoked during the GABA(D) component of a spontaneous GPSC was an outward current. To test whether the siGPSC lacked a GABA(D) component because it was generated predominantly at the soma, where less of an increase in [Cl-](i) would occur, picrotoxin was applied to the soma of the pyramidal cell. To the contrary, this focal application of picrotoxin caused less of a reduction in the amplitude of the siGPSC than in the amplitude of the GABA(A) component of the GPSC. Furthermore when a GPSC and siGPSC were evoked 10 s apart using identical stimuli, the area under the outward current curve was sometimes greater for the siGPSC than for the GPSC, and yet the siGPSC had no inward component. This result indicates that even when the location of Cl- entry was the same, more Cl- could enter the cell during the siGPSC than during the outward component of the GPSC and yet not lead to an inward current. In addition, when the second of two identical stimuli was applied during the inward GABA(D) component of the first evoked GPSC, the GABA(A) response it generated was always outward, demonstrating that the equilibrium potential for GABA(A) responses did not become more positive than the holding potential during a GPSC. Finally, evoking GPSCs at a hyperpolarized potential revealed that the siGPSC actually lacked a GABA(D) conductance. These results disprove the Cl- accumulation hypothesis of the synaptic depolarizing GABA response and suggest the possibility that a separate channel type may mediate the GABA(D) component of the GPSC. (+info)
Cortical integration in the visual system of the macaque monkey: large-scale morphological differences in the pyramidal neurons in the occipital, parietal and temporal lobes.
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Layer III pyramidal neurons were injected with Lucifer yellow in tangential cortical slices taken from the inferior temporal cortex (area TE) and the superior temporal polysensory (STP) area of the macaque monkey. Basal dendritic field areas of layer III pyramidal neurons in area STP are significantly larger, and their dendritic arborizations more complex, than those of cells in area TE. Moreover, the dendritic fields of layer III pyramidal neurons in both STP and TE are many times larger and more complex than those in areas forming 'lower' stages in cortical visual processing, such as the first (V1), second (V2), fourth (V4) and middle temporal (MT) visual areas. By combining data on spine density with those of Sholl analyses, we were able to estimate the average number of spines in the basal dendritic field of layer III pyramidal neurons in each area. These calculations revealed a 13-fold difference in the number of spines in the basal dendritic field between areas STP and V1 in animals of similar age. The large differences in complexity of the same kind of neuron in different visual areas go against arguments for isopotentiality of different cortical regions and provide a basis that allows pyramidal neurons in temporal areas TE and STP to integrate more inputs than neurons in more caudal visual areas. (+info)
Reduced K+ channel inactivation, spike broadening, and after-hyperpolarization in Kvbeta1.1-deficient mice with impaired learning.
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A-type K+ channels are known to regulate neuronal firing, but their role in repetitive firing and learning in mammals is not well characterized. To determine the contribution of the auxiliary K+ channel subunit Kvbeta1.1 to A-type K+ currents and to study the physiological role of A-type K+ channels in repetitive firing and learning, we deleted the Kvbeta1.1 gene in mice. The loss of Kvbeta1.1 resulted in a reduced K+ current inactivation in hippocampal CA1 pyramidal neurons. Furthermore, in the mutant neurons, frequency-dependent spike broadening and the slow afterhyperpolarization (sAHP) were reduced. This suggests that Kvbeta1.1-dependent A-type K+ channels contribute to frequency-dependent spike broadening and may regulate the sAHP by controlling Ca2+ influx during action potentials. The Kvbeta1.1-deficient mice showed normal synaptic plasticity but were impaired in the learning of a water maze test and in the social transmission of food preference task, indicating that the Kvbeta1.1 subunit contributes to certain types of learning and memory. (+info)
Deficits in memory tasks of mice with CREB mutations depend on gene dosage.
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Studies in Aplysia, Drosophila, and mice have shown that the transcription factor CREB is involved in formation and retention of long-term memory. To analyze the impact of differential CREB levels on learning and memory, we varied the gene dosage of CREB in two strains of mutant mice: (1) CREBalphadelta mice, in which the alpha and delta isoforms are disrupted, but a third isoform beta is strongly up-regulated; (2) CREBcomp, a compound strain with one alphadelta allele and one CREBnull allele in which all CREB isoforms are disrupted. To minimize genetic background effects, CREB mutations were backcrossed into a C57BL/6 and a FVB/N strain, respectively, and studies were performed in F1 hybrids from these lines. CREBcomp but not CREBalphadelta F1 hybrids were impaired in water maze learning and fear conditioning, demonstrating a CREB gene dosage effect. However, analysis of the platform searching strategies in the water maze task suggested that CREBcomp mutants are impaired in behavioral flexibility rather than in spatial memory. In contrast to previous experiments using CREBalphadelta mice with different genetic background, the F1 hybrid CREBalphadelta and CREBcomp mice did not show deficits in a social transmission of food preference task nor in dentate gyrus and CA1 LTP as recorded from slice preparations. These data indicate that the hybrid vigor typical for F1 hybrids may compensate for a reduction in CREB levels in some tests. On the other hand, the persistence of clear behavioral deficits as shown by the F1 hybrid CREBcomp mice in water maze and fear conditioning indicates a robust and repeatable phenomenon that will permit further functional analysis of CREB. (+info)
Enhanced hippocampal CA1 LTP but normal spatial learning in inositol 1,4,5-trisphosphate 3-kinase(A)-deficient mice.
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To define the physiological role of IP(3)3-kinase(A) in vivo, we have generated a mouse strain with a null mutation of the IP(3)3-kinase(A) locus by gene targeting. Homozygous mutant mice were fully viable, fertile, apparently normal, and did not show any morphological anomaly in brain sections. In the mutant brain, the IP4 level was significantly decreased whereas the IP3 level did not change, demonstrating a major role of IP(3)3-kinase(A) in the generation of IP4. Nevertheless, no significant difference was detected in the hippocampal neuronal cells of the wild-type and the mutant mice in the kinetics of Ca2+ regulation after glutamate stimulation. Electrophysiological analyses carried out in hippocampal slices showed that the mutation significantly enhanced the LTP in the hippocampal CA1 region, but had no effect on the LTP in dentate gyrus (DG). No difference was noted, however, between the mutant and the wild-type mice in the Morris water maze task. Our results indicate that IP(3)3-kinase(A) may play an important role in the regulation of LTP in hippocampal CA1 region through the generation of IP4, but the enhanced LTP in the hippocampal CA1 does not affect spatial learning and memory. (+info)
Selective abolition of the NMDA component of long-term potentiation in mice lacking mGluR5.
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The mechanisms underlying the differential expression of long-term potentiation (LTP) by AMPA and NMDA receptors, are unknown, but could involve G-protein-linked metabotropic glutamate receptors. To investigate this hypothesis we created mutant mice that expressed no metabotropic glutamate receptor 5 (mGluR5), but showed normal development. In an earlier study of these mice we analyzed field-excitatory postsynaptic potential (fEPSPs) in CA1 region of the hippocampus and found a small decrease; possibly arising from changes in the NMDAR-mediated component of synaptic transmission. In the present study we used whole-cell patch clamp recordings of evoked excitatory postsynaptic currents (EPSCs) in CA1 pyramidal neurons to identify the AMPAR- and NMDAR-mediated components of LTP. Recordings from control mice following tetanus, or agonist application (IS, 3R-1-amino-cyclopentane 1,3-dicarboxylic acid) (ACPD), revealed equal enhancement of the AMPA and NMDA receptor-mediated components. In contrast, CA1 neurons from mGluR5-deficient mice showed a complete loss of the NMDA-receptor-mediated component of LTP (LTP(NMDA)), but normal LTP of the AMPA-receptor-mediated component (LTP(AMPA)). This selective loss of LTP(NMDA) was seen in three different genotypic backgrounds and was apparent at all holding potentials (-70 mV to +20 mV). Furthermore, the LTP(NMDA) deficit in mGluR5 mutant mice could be rescued by stimulating protein kinase C (PKC) with 4beta-phorbol-12,13-dibutyrate (PDBu). These results suggest that PKC may couple the postsynaptic mGluR5 to the NMDA-receptor potentiation during LTP, and that this signaling mechanism is distinct from LTP(AMPA). Differential enhancement of AMPAR and NMDA receptors by mGluR5 also supports a postsynaptic locus for LTP. (+info)