Multideterminant role of calcium in hippocampal synaptic plasticity.

Hippocampal CA1 cells possess several varieties of long-lasting synaptic plasticity: two different forms of long-term potentiation (LTP) and at least one form of long-term depression (LTD). All forms of synaptic plasticity are induced by afferent activation, all involve Ca2+ influx, all can be blocked by Ca2+ chelators, and all activate Ca(2+)-dependent mechanisms. The question arises as how different physiological responses can be initiated by activation of the same second messenger. We consider two hypotheses which could account for these phenomena: voltage-dependent differences in cytosolic Ca2+ concentration acting upon Ca2+ substrates of differing Ca2+ affinities and compartmentalization of the Ca2+ and its substrates.

Development of inhibitory and excitatory synaptic transmission in the rat dentate gyrus.

We studied the ontogeny of inhibitory and excitatory processes in the rat dentate gyrus by examining paired-pulse plasticity in the hippocampal slice preparation. The mature dentate gyrus produces characteristic paired-pulse responses across a wide range of interpulse intervals (IPI). Paired-pulse effects on population excitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitude were analyzed at postnatal day 6 (PN6), PN7/8, PN9/10, PN15/16, and PN > 60. The synaptic paired-pulse profile (10-5,000 ms IPI) matured by PN7/8. The triphasic pattern of short-latency depression, a relative facilitation at intermediate intervals, and long-latency depression was present at all ages tested. Paired-pulse effects on granule cell discharge indicated the presence of weak short-latency (20 ms IPI) inhibition at PN6, the earliest day that a population spike could be evoked. By PN7/8, short-latency inhibition was statistically equivalent to the mature dentate gyrus. Long-latency (500-2,000 ms IPI) PS inhibition was present, and equal to the mature dentate gyrus by PN6. The most consistent difference between the mature and developing dentate gyrus occurred at intermediate IPIs (40-120 ms) where spike facilitation was significantly depressed in the development groups. The studies indicate that short-term plasticity matures rapidly in the dentate gyrus and suggest that the inhibitory circuitry can function at a surprisingly early age.

Spermine depresses NMDA, K/AMPA and GABAA-mediated synaptic transmission in the rat hippocampal slice preparation.

The effects of spermine, an endogenous polyamine, were examined in area CA1 of the rat hippocampal slice preparation. Spermine, at low millimolar concentrations, rapidly and potently depressed NMDA and K/AMPA-mediated population EPSPs, and GABA-mediated monosynaptic population IPSPs. These effects contrast with its well-known potentiation of NMDA currents at lower concentrations. Our results raise the possibility that the large intracellular stores of spermine that are released after various neural insults could act as an endogenous neuroprotective mechanism by limiting excessive calcium entry.

The development of GABAB-mediated activity in the rat dentate gyrus.

We examined the effects of GABAB receptor activation in the dentate gyrus of hippocampal slices prepared from 6-8-day-old rat pup. Baclofen (0.25-1.0 microM), a GABAB agonist, rapidly and potently disinhibited the developing dentate, similar to its effect in the mature organism. CGP 35348, a GABAB antagonist, quickly reversed the baclofen-induced disinhibition. However, GABAB antagonists did not reverse long-latency (500-1000 ms IPI) paired-pulse depression, suggesting that it is not caused by a late GABAB-mediated IPSP. GABAB-mediated disinhibition of the dentate gyrus can occur by postnatal day 6, providing a powerful mechanism for altering excitability in the developing hippocampus.

alpha-Difluoromethylornithine decreases inhibitory transmission in hippocampal slices independently of its inhibitory effect on ornithine decarboxylase.

We tested the effect of DL-alpha-(difluoromethyl)ornithine (DFMO), a specific inhibitor of ornithine decarboxylase (ODC), on recordings in area CA1 of rat hippocampal slices. In the concentration range in which it is used as an ODC inhibitor, DFMO increased neuronal excitability and blocked paired-pulse inhibition. The effect of DFMO was reversed by perfusing the slice with normal bathing solution. These effects were not attenuated by the simultaneous addition of putrescine; thus the activity of DFMO was not related to a decrease in putrescine caused by the inhibition of ODC. Mediation by the N-methyl-D-aspartate (NMDA) receptor was ruled out because DL-2-amino-5-phosphonovalerate (APV), an NMDA antagonist, did not block the effect of DFMO. Intracellular and extracellular recordings of pharmacologically isolated IPSPs supported the notion that DFMO depressed GABAergic transmission. DFMO has frequently been used as a tool to study the role of the ODC-polyamine system in neural preparations. This report suggests that the results from such studies must be interpreted with caution. In addition, our findings raise questions about the proposed use of DFMO as a neuroprotective agent against excitotoxicity.

A method for calculating current source density (CSD) analysis without resorting to recording sites outside the sampling volume.

This article is part of a study on cortical microcircuitry in which flash evoked potentials (FEPs) were recorded from the anesthetized rat visual cortex. The FEPs were subjected to current source density analysis (CSD). One of the limitations of the CSD method is the need for recording sites outside the sampling volume, in order to obtain a full description of the CSD distribution. This problem is acute in the neocortex where a tissue/fluid boundary exists. A simple solution is provided based on the fact that the field potentials decay minimally under the conditions of these experiments. In the neocortex the most superficial recording site and the deepest recording site are used to provide the extra recording sites necessary to obtain a full description of the CSD distribution. This approach when tested by summing the current sinks and sources across all layers of cortex produces excellent results, with significant reduction of the residual sinks and sources.

The hippocampal memory indexing theory.

The hippocampal formation (comprising the hippocampus proper, the dentate gyrus, and the subiculum) has been repeatedly implicated in information storage models of the mammalian brain. The precise nature of the hippocampal role in the storage of information has, however, remained elusive. Here it is proposed that the role of the hippocampus is to form and retain an index of neocortical areas activated by experiential events. The hippocampal index, thus, represents those unique cortical regions activated by specific events. The neuronal mechanism underlying the memory index is hypothesized to be long-term potentiation. It is asserted that the reactivation of the stored hippocampal memory index will serve to also reactivate the associated unique array of neocortical areas and thus will result in a memorial experience. This hippocampal reactivation of a neocortical array may also be involved in establishing a cortically based memory trace.

The role of hippocampus in memory: a hypothesis.

The role of the hippocampus in memory storage in the mammalian brain is examined. The intrinsic anatomical organization of the hippocampus is such that a multidimensional mapping of other brain regions is represented. Emerging knowledge of the cortico-limbic-subcortical anatomy suggests that the hippocampal representations preserve the topological features of the targets and possess reciprocal connectivity. Long-Term Potentiation (LTP) is a prominent physiological characteristic of hippocampal synapses and is a promising candidate mnemonic device. The hypothesis is advanced that the pattern, or index, of specific neocortical (and other) areas activated by an experiential event is represented, or indexed, in the hippocampus by means of LTP. This hypothesis, termed the Memory Indexing Theory, suggests that experiential events are initially stored in an index of neocortical locations maintained in hippocampus. Subsequently, other regions, notably neocortex itself, permanently encode these experiential events and the interrelationships between them.

The topological anatomy of the hippocampus: a clue to its function.

The anatomy of the hippocampus and dentate gyrus is considered with respect to the topology of its afferents and efferents. The topological attributes of the hippocampal formation represent a four-dimensional array with the demensions being: the afferent input to laminated dendritic zones, the intrinsic tri-synaptic hippocampal system, the longitudinal and commissural association systems, and time. Within this four-dinmensional array, active foci can vary dynamically in space and time, depending upon the pattern of afferent activity. The features of hippocampal topology may relate to the role of the hippocampal formation in information storage and processing.

Long-term potentiation as a candidate mnemonic device.

One approach to studying the neurophysiological correlates of long-term memory is to search for, and study properties of the nervous system that impart plasticity of synaptic efficacy. Within this context, we argue that long-term potentiation is, currently, the most plausible device for subserving or initiating long-term information storage in the mammalian brain. This argument is derived from examining features of LTP with respect to the constraints posed by our current concepts of learning and memory. In addition, we examine evidence for a role by LTP in behavioral learning. We conclude that studying LTP within the context of behavioral learning and memory may provide new insights into the neurophysiological bases of learning and memory.