Serotonergic modulation of evoked responses in the hippocampal formation of the rat
Creators: name: Klancnik, Joseph Mario
Publisher: name: University of British Columbia
Year: 2010

description: The diffuse ascending projections of serotonin-containing nuclei in the brainstem have suggested a role for these structures in the control of forebrain systems. The hippocampal formation (HF) receives dense serotonergic projections from the dorsal and medial raphe nuclei and contains high concentrations of serotonergic binding sites, and is therefore an appropriate region of the brain in which to study serotonergic processes. The purpose of the experiments discussed in this dissertation was to investigate the influence of the serotonergic system on the electrophysiological activity of the HF, with especial emphasis on the dentate gyrus (DG). In all of the experiments, evoked population responses were used as a measure of synaptic transmission. The first two series of experiments investigated the effects of serotonin and serotonergic compounds on evoked responses, in both in vitro and in vivo preparations. The third series of experiments investigated the role of the median raphe nucleus (MRN), the major source of serotonergic afferents to the HF, on synaptic plasticity in the DG. The first series of experiments, described in Chapter 2, compared the effects of serotonin, the 5-HT[sub 1A] receptor subtype agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and the 5-HT₂ receptor subtype agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on electrophysiological responses in the dentate gyrus and CA1 regions of the HF, using the in vitro hippocampal slice preparation. Bath superfusion of either serotonin or 8-OH-DPAT was found to inhibit population responses in a dose-dependent manner in both regions, with a greater effect in the CAl. The effects of 8-OH-DPAT in both regions could be attenuated significantly by the serotonergic antagonist methysergide, as could the effects of 5-HT in the CA1. The application of DOI did not produce statistically significant effects in either region, although an inhibitory effect on DG responses was observed in some preparations. These findings support an inhibitory role for the 5-HT[sub 1A] receptor in both the CA1 and the DG, and possibly for the 5-HT₂ receptor in the DG, indicating that the endogenous serotonergic system may serve to inhibit neural transmission in both of these regions. The second series of experiments, described in Chapter 3, examined the effects of serotonergic agents on electrophysiological responses in the DG in an anaesthetized, in vivo rat preparation. In contrast to the results of the in vitro experiments, intraperitoneal injections of either 5-hydroxytryptophan (5-HTP, the metabolic precursor to 5-HT) or 8-OH-DPAT were found to facilitate the amplitude of the population spike in the DG. Intravenous (i.v.) administration of 8-OH-DPAT was also found to increase population spike amplitude (PSA), although an attenuated effect was observed at high doses. Increases in PSA were also observed following microinjections of 8-OH-DPAT either into the lateral ventricle, or directly into the vicinity of the median raphe nucleus (MRN), suggesting that the effects of 8-OH-DPAT observed in vivo are due largely to action on presynaptic 5-HT[sub 1A] receptors located on serotonergic neurons. This suggestion was supported by the finding that pre treatment with the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) attenuated the effects of i.v. 8-OH-DPAT significantly. As 5-HT[sub 1A] receptors on the 5-HT neurons are thought to be inhibitory, these experiments indicate that 8-OH-DPAT acts to attenuate a tonic inhibitory influence which the MRN neurons exert on the DG. Intravenous administration of the 5-HT[sub 1A] ligands buspirone or BMY-7378 also appeared to produce dose-dependent increases in PSA, although these effects were found not to be statistically significant; intravenous administration of the 5-HT₂ agonist DOI did not produce any discernable effects on population responses, indicating that the 5-HT₂ receptor may not play a functional role in the DG. The experiments in Chapter 4 examined the possible modulation of synaptic plasticity in the DG by serotonergic afferents from the MRN. High-frequency (tetanic) stimulation of the major afferent projection to the DG, the perforant path (PP), is known to produce a long-lasting increase in synaptic efficacy at the PP-DG synapse, a phenomenon known as long-term potentiation (LTP), which has been considered as a possible biological substrate of memory formation. In the experiments in this section, the magnitude of LTP was found to be enhanced significantly when tetanic stimulation was applied to the MRN and PP concurrently, as compared to when tetanic stimulation was applied to the PP alone. These results indicate a modulatory influence of ascending serotonergic projections on synaptic plasticity in the HF. Together, the pharmacological experiments performed in vitro and in vivo indicate that the endogenous serotonergic system acts to inhibit synaptic transmission in the HF, and therefore possibly information processing in this forebrain structure. Furthermore, the facilitation of LTP by MRN stimulation suggests a role for the serotonergic system in the modulation of long-lasting changes in synaptic efficacy in the DG. As the activity of serotonergic neurons in the raphe nuclei is known to vary with levels of arousal, this could provide a mechanism by which the functioning of the hippocampus may be modified in acccordance with behavioural state.