Effect of norepinephrine depletion of hippocampus on neuronal transmission from perforant pathway through dentate gyrus.

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Abstract
Granule cell response to perforant path stimulation was studied in freely moving rats depleted of hippocampal norepinephrine (NE) by prior intracerebral injection of 6-hydroxydopamine (6-OHDA) as well as in untreated control animals. Experiments were performed under 2 behavioral conditions: slow-wave sleep (SWS) and the still-alert state (SAL). In each behavior, electrical stimulation was applied to the perforant pathway and monosynaptic evoked responses were recorded extracellularly in the ipsilateral dentate gyrus. Two types of evoked responses were recorded: those due to the synchronous firing of granule cell action potentials (evoked action potentials; EAP) and those produced by excitatory synaptic activity (evoked synaptic potentials or ESP). In some tests, stimulation was also applied to the region of the median raphe nucleus prior to activating the perforant pathway. In normal animals, EAP recorded in the granule cell layer were significantly greater during SWS than during SAL. In rats with NE depletions in excess of 90% of normal levels, this consistent difference in EAP response with behavior was no longer apparent. There either was no significant difference between EAP responses during SWS and SAL or, in a given animal, the EAP responses during 1 of the 2 behaviors were marginally greater than the responses in the other. In normal rats, ESP recorded in the granule cell molecular layer after perforant path stimulation were greater during SAL than during SWS. Animals depleted of hippocampal NE (.gtoreq. 96% levels) there was no difference in the ESP recorded during the 2 behavioral states. Prestimulation of the median raphe nucleus in norepinephrine-depleted rats produced a similar but considerably smaller enhancement of the EAP during SWS as compared to SAL. Rats depleted of serotonin [5-hydroxytryptamine (5-HT)] by systemic injection of p-chloroamphetamine (PCA) showed no difference in EAP responses during SWS and SAL. Differences in ESP responses seen in normal animals (SAL > SWS) were also observed in these depleted rats. The present experiment indicates that the decreased tendency of granule cells to fire following a perforant path volley (decreased EAP) during SAL as compared to SWS as well as the increased flow of extracellular current in the molecular layer of the dentate gyrus (increased ESP) during SAL as compared to SWS are eliminated by depletion of hippocampal norepinephrine. Since norepinephrine-containing cells of locus ceruleus are known to fire preferentially during the still-alert state (7,8), we suggest that locus ceruleus innervation of granule cells during this behavior may, at least in part, be responsible for producing these effects in the intact animal. The present findings also suggest that norepinephrine innervation of granule cells during SAL may play a role in the relative suppression of granule cell firing during SAL as compared to SWS in experiments in which prestimulation is applied to the median raphe nucleus.

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