Nonlinear frequency-dependent synchronization in the developing hippocampus.
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Synchronous population activity is present both in normal and pathological conditions such as epilepsy. In the immature hippocampus, synchronous bursting is an electrophysiological conspicuous event. These bursts, known as giant depolarizing potentials (GDPs), are generated by the synchronized activation of interneurons and pyramidal cells via GABAA, N-methyl-D-aspartate, and AMPA receptors. Nevertheless the mechanism leading to this synchronization is still controversial. We have investigated the conditions under which synchronization arises in developing hippocampal networks. By means of simultaneous intracellular recordings, we show that GDPs result from local cooperation of active cells within an integration period prior to their onset. During this time interval, an increase in the number of excitatory postsynaptic potentials (EPSPs) takes place building up full synchronization between cells. These EPSPs are correlated with individual action potentials simultaneously occurring in neighboring cells. We have used EPSP frequency as an indicator of the neuronal activity underlying GDP generation. By comparing EPSP frequency with the occurrence of synchronized GDPs between CA3 and the fascia dentata (FD), we found that GDPs are fired in an all-or-none manner, which is characterized by a specific threshold of EPSP frequency from which synchronous GDPs emerge. In FD, the EPSP frequency-threshold for GDP onset is 17 Hz. GDPs are triggered similarly in CA3 by appropriate periodic stimulation of mossy fibers. The frequency threshold for CA3 GDP onset is 12 Hz. These findings clarify the local mechanism of synchronization underlying bursting in the developing hippocampus, indicating that GDPs are fired when background levels of EPSPs or action potentials have built up full synchronization by firing at specific frequencies (>12 Hz). Our results also demonstrate that spontaneous EPSPs and action potentials are important for the initiation of synchronous bursts in the developing hippocampus. (+info)
Rapid and slow swelling during hypoxia in the CA1 region of rat hippocampal slices.
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The role of swelling in hypoxic/ischemic neuronal injury is incompletely understood. We investigated the extent and time course of cell swelling during hypoxia, and recovery of cell volume during reoxygenation, in the CA1 region of rat hippocampal slices in vitro. Cell swelling was measured optically and compared with simultaneous measurements of the extracellular DC potential, extracellular [K+], and synaptic transmission in the presence and absence of hypoxic depolarization. Hypoxia-induced swelling consisted of rapid and/or slow components. Rapid swelling was observed frequently and always occurred simultaneously with hypoxic depolarization. Additionally, rapid swelling was followed by a prolonged phase of swelling that was approximately 15 times slower. Less frequently, slow swelling occurred independently, without either hypoxic depolarization or a preceding rapid swelling. For slices initially swelling rapidly, recovery of both cell volume and the slope of field excitatory postsynaptic potentials were best correlated with the duration of hypoxia (r = 0.77 and 0.87, respectively). This was also the case for slices initially swelling slowly (r = 0.70 and 0.58, respectively). In contrast, the degree of recovery of cell volume was the same at 30 or 60 min of reoxygenation, indicating that prolonging the duration of reoxygenation within these limits was ineffective in improving recovery. Spectral measurements indicated that the hypoxia-induced changes in light transmittance were related to changes in cell volume and not changes in the oxidation state of mitochondrial cytochromes. The persistent impairment of synaptic transmission in slices swelling slowly (i.e., without hypoxic depolarization) indicates that swelling may play a role in this injury and that hypoxic depolarization is not required. Additionally, the correlation between the degree of recovery of cell volume and the degree of recovery of synaptic transmission during reoxygenation supports a role for swelling in hypoxic neuronal injury. (+info)
Molecular determinants for subcellular localization of PSD-95 with an interacting K+ channel.
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Ion channels and PSD-95 are colocalized in specific neuronal subcellular locations by an unknown mechanism. To investigate mechanisms of localization, we used biolistic techniques to express GFP-tagged PSD-95 (PSD-95:GFP) and the K(+)-selective channel Kv1.4 in slices of rat cortex. In pyramidal cells, PSD-95:GFP required a single PDZ domain and a region including the SH3 domain for localization to postsynaptic sites. When transfected alone, PSD-95:GFP was present in dendrites but absent from axons. When cotransfected with Kv1.4, PSD-95:GFP appeared in both axons and dendrites, while Kv1.4 was restricted to axons. When domains that mediate the interaction of Kv1.4 and PSD-95 were disrupted, Kv1.4 localized nonspecifically. Our results provide evidence that Kv1.4 itself may determine its subcellular location, while an associated MAGUK protein is a necessary but not sufficient cofactor. (+info)
Multiple forms of LTP in hippocampal CA3 neurons use a common postsynaptic mechanism.
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We investigated long-term potentiation (LTP) at mossy fiber synapses on CA3 pyramidal neurons in the hippocampus. Using Ca2+ imaging techniques, we show here that when postsynaptic Ca2+ was sufficiently buffered so that [Ca2+]i did not rise during synaptic stimulation, the induction of mossy fiber LTP was prevented. In addition, induction of mossy fiber LTP was suppressed by postsynaptic injection of a peptide inhibitor of cAMP-dependent protein kinase. Finally, when ionotropic glutamate receptors were blocked, LTP depended on the postsynaptic release of Ca2+ from internal stores triggered by activation of metabotropic glutamate receptors. These results support the conclusion that mossy fiber LTP and LTP at other hippocampal synapses share a common induction mechanism involving an initial rise in postsynaptic [Ca2+]. (+info)
Glutamate receptors mediate TTX-resistant synchronous activity in the rat hippocampus.
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4-Aminopyridine (4-AP) is a well known convulsant that enhances the release of both excitatory and inhibitory neurotransmitters in the CNS. Low concentrations of 4-AP (approximately 100 microM) readily induce synchronized discharges in the hippocampus that are blocked by tetrodotoxin (TTX), suggesting that they require Na(+)-dependent action potentials in addition to the enhanced release of neurotransmitters. However, in the present study we have found that higher concentrations of 4-AP (1 mM) in combination with 5 mM tetraethylammonium (TEA) induce spontaneous synchronized discharges in rat hippocampal slices that are resistant to blockade by TTX. These synchronous discharges are evident in field potential recordings, which progress from the hilus to CA1 at 0.023 +/- 0.002 m/sec and in intracellular recordings from the hilar mossy cells and CA3 pyramidal cells. In some slices exposed to 4-AP and TEA, smaller-amplitude asynchronous responses also were recorded. 4-AP-induced spontaneous discharges are blocked by 20 microM DNQX and by 100 microM Cd(2+) but are resistant to blockade by either 25 microM bicuculline or 25 microM D-APV. These results suggest that the activation of postsynaptic AMPA receptors is necessary to produce TTX-resistant synchronized discharges. The laminar profile of field potentials recorded in CA3 and CA1 suggests that glutamate is released from axons of CA3 pyramidal cells despite the blockade of fast axonal Na(+) channels by TTX. Synchronous discharges may result from glutamate released at proximal recurrent collaterals after spontaneous Ca(2+) spikes in CA3 pyramidal cells. (+info)
Interactions between hippocampus and medial septum during sharp waves and theta oscillation in the behaving rat.
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The medial septal region and the hippocampus are connected reciprocally via GABAergic neurons, but the physiological role of this loop is still not well understood. In an attempt to reveal the physiological effects of the hippocamposeptal GABAergic projection, we cross-correlated hippocampal sharp wave (SPW) ripples or theta activity and extracellular units recorded in the medial septum and diagonal band of Broca (MSDB) in freely moving rats. The majority of single MSDB cells (60%) were significantly suppressed during SPWs. Most cells inhibited during SPW (80%) fired rhythmically and phase-locked to the negative peak of the CA1 pyramidal layer theta waves. Because both SPW and the negative peak of local theta waves correspond to the maximum discharge probability of CA1 pyramidal cells and interneuron classes, the findings indicate that the activity of medial septal neurons can be negatively (during SPW) or positively (during theta waves) correlated with the activity of hippocampal interneurons. We hypothesize that the functional coupling between medial septal neurons and hippocampal interneurons varies in a state-dependent manner. (+info)
Interdependence of multiple theta generators in the hippocampus: a partial coherence analysis.
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The extracellularly recorded theta oscillation reflects a dynamic interaction of various synaptic and cellular mechanisms. Because the spatially overlapping dipoles responsible for the generation of theta field oscillation may represent different mechanisms, their separation might provide clues with regard to their origin and significance. We used a novel approach, partial coherence analysis, to reveal the various components of the theta rhythm and the relationship among its generators. Hippocampal field activity was recorded by a 16-site silicon probe in the CA1-dentate gyrus axis of the awake rat. Field patterns, recorded from various intrahippocampal or entorhinal cortex sites, were used to remove activity caused by a common source by the partialization procedure. The findings revealed highly coherent coupling between theta signals recorded (1) from the hippocampal fissure and stratum (str.) oriens of the CA1 region and (2) between CA1 stratum radiatum and the dentate molecular layer. The results of partial coherence analysis indicated that rhythmic input from the entorhinal cortex explained theta coherence between signals recorded from the hippocampal fissure and str. oriens but not the coherence between signals derived from str. radiatum and the dentate molecular layer. After bilateral lesions of the entorhinal cortex, all signals recorded from both below and above the CA1 hippocampal pyramidal cell layer became highly coherent. These observations indicate the presence of two, relatively independent, theta generators in the hippocampus, which are mediated by the entorhinal cortex and the CA3-mossy cell recurrent circuitry, respectively. The CA3-mossy cell theta generator is partially suppressed by the dentate gyrus interneuronal output in the intact brain. We suggest that timing of the action potentials of pyramidal cells during the theta cycle is determined by the cooperation between the active CA3 neurons and the entorhinal input. (+info)
Febrile seizures in the developing brain result in persistent modification of neuronal excitability in limbic circuits.
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Febrile (fever-induced) seizures affect 3-5% of infants and young children. Despite the high incidence of febrile seizures, their contribution to the development of epilepsy later in life has remained controversial. Combining a new rat model of complex febrile seizures and patch clamp techniques, we determined that hyperthermia-induced seizures in the immature rat cause a selective presynaptic increase in inhibitory synaptic transmission in the hippocampus that lasts into adulthood. The long-lasting nature of these potent alterations in synaptic communication after febrile seizures does not support the prevalent view of the 'benign' nature of early-life febrile convulsions. (+info)