Spontaneous waves in the dentate gyrus of slices from the ventral hippocampus.

Spontaneous negative-going potentials occurring at an average frequency of 0.7 Hz were recorded from the dentate gyrus of slices prepared from the temporal hippocampus of young adult rats. These events (here termed "dentate waves") in several respects resembled the dentate spikes described for freely moving rats during immobile behaviors and slow-wave sleep. Action potentials were observed on the descending portion of the in vitro waves and, as expected from this, whole cell recordings established that the waves were composed of depolarizing currents. Dentate waves appeared to be locally generated within the granule cell layer and were greatly reduced by antagonists of AMPA-type glutamate receptors or by lesions to the entorhinal cortex. Simultaneous recordings indicated that the waves were often synchronized in the inner and outer blades of the dentate gyrus. Knife cuts through the perforant path and the commissural/associational system did not eliminate synchronization, leaving electrotonic propagation via gap junctions as its probable cause. In accord with this, cuts that separated the two blades of the dentate eliminated synchronization between them, and a compound that inhibits gap junctions reduced wave activity. Dentate waves were regularly accompanied by sharp waves in field CA3 and were reduced in size by the acetylcholinesterase inhibitor, physostigmine. It is hypothesized that dentate waves occur when spontaneous glutamate release from dentate afferents produces action potentials in neighboring granule cells that then summate electrotonically into a population event; once initiated, the waves propagate, again electrotonically, and thereby engage a significant portion of the granule cell population.

Long-term potentiation is impaired in rat hippocampal slices that produce spontaneous sharp waves.

Sharp waves (SPWs) occur in the hippocampal EEG during behaviours such as alert immobility and slow-wave sleep. Despite their widespread occurrence across brain regions and mammalian species, the functional importance of SPWs remains unknown. Experiments in the present study indicate that long-term potentiation (LTP) is significantly impaired in slices, prepared from the temporal aspect of rat hippocampus, that spontaneously generate SPW activity. This was probably not due to anatomical and/or biochemical abnormalities in temporal slices because stable LTP was uncovered in field CA1 when SPWs were eliminated by severing the projection from CA3. The same procedure did not alter LTP in slices lacking SPWs. Robust and stable LTP was obtained in the presence of SPWs in slices treated with an adenosine A1 receptor antagonist, a finding that links the present results to mechanisms related to the LTP reversal effect. In accord with this, single stimulation pulses delivered intermittently in a manner similar to the SPW pattern interfered with LTP to a similar degree as spontaneous SPWs. Taken together, these results suggest the possibility that SPWs in the hippocampus constitute a neural mechanism for forgetting.

Cholinergic plasticity in the hippocampus.

Tests were made for use-dependent plasticity in the cholinergic projections to hippocampus. Transient infusion of the cholinergic agonist carbachol into hippocampal slices induced rhythmic activity that persisted for hours after washout. Comparable effects were obtained with physostigmine, a drug that blocks acetylcholine breakdown and thereby enhances cholinergic transmission. It thus seems that activation of cholinergic synapses induces lasting changes in hippocampal physiology. Two lines of evidence indicated that cholinergic synapses are also the sites at which the plasticity is expressed. First, the induction and expression of the rhythms were not blocked by the N-methyl-D-aspartate receptor antagonist D-2-amino-5-phosphonovaleric acid, indicating that a long-term potentiation effect between pyramidal cells was not involved. Second, a muscarinic antagonist (atropine) completely abolished stable rhythmic activity after agonist washout. This result indicates that endogenous cholinergic activity is responsible for the persistence of rhythmic oscillations. These experiments suggest that short periods of intense cholinergic activity induce lasting changes in cholinergic synapses and thus extend such forms of plasticity to beyond the glutamatergic system.

Endogenous waves in hippocampal slices.

Sharp waves (SPWs) are thought to play a major role in intrinsic hippocampal operations during states in which subcortical and cortical inputs to hippocampus are reduced. This study describes evidence that such activity occurs spontaneously in appropriately prepared rat hippocampal slices. Irregular waves, with an average frequency of approximately 4 Hz, were recorded from field CA3 in slices prepared from the temporal region of hippocampus. The waves persisted for hours and were not accompanied by aberrant discharges. Multi-electrode analyses established that they were locally generated within each of the subfields of CA3 and yet were coherent between subfields. The sharp waves were reversibly blocked by either cholinergic or serotonergic stimulation. Various lines of evidence indicate that they are propagated by the CA3 associational system.

Asymmetrical distribution of the Schaffer projections within the apical dendrites of hippocampal field CA1.

Continuous current source densities were calculated in two dimensions (proximo-distal vs. medio-lateral) from slices of hippocampal field CA1 placed on a 64-electrode array in the presence of GABA blockers. The synaptic sink generated by stimulation of the Schaffer-commissural fibers spread across the extent of field CA1 within the same sublamina of the stratum radiatum as the stimulation electrode. The size and shape of the current sink varied according to the proximo-distal position of the stimulation site. Sinks generated by stimulation close to the cell body layer were more compact when compared to those produced by stimulation near the top of stratum radiatum which were broad and skewed in the proximal direction. These distributions were obtained with stimulation at either the CA3 or the subicular border of CA1. Induction of LTP increased the intensity of the current field but did not notably affect its distribution. It is concluded that (1) axons remain at the same proximo-distal level as they traverse stratum radiatum of CA1 and (2) generate proximally directed collaterals. Because of this, fibers that enter CA1 stratum radiatum immediately above the pyramidal cell bodies form compact synaptic fields while those entering CA1 at the top of the lamina form much broader and asymmetrical distributed fields.