Effects of 5-HT3 receptor antagonism on hippocampal theta rhythm, memory, and LTP induction in the freely moving rat

Abstract

Serotonergic brainstem projections to hippocampus are thought to preferentially target and increase, via 5-HT3 receptors, the excitability of a distinct subpopulation of interneurons that primarily regulate GABAB-mediated inhibition in the dendritic region of pyramidal cells. Hippocampal slice work suggests that the between-burst hyperpolarization caused by slow (GABAB) IPSPs plays a significant role in controlling the strength of LTP induced with theta burst stimulation. According to the above observations it was assumed that blockade of hippocampal 5-HT3 receptors should reduce the hyperpolarization and thereby enhance both the frequency of the naturally occurring theta rhythm and the induction of LTP; moreover, if LTP-like mechanisms provide the substrate for certain forms of memory, such treatment was expected to facilitate learning. Each of the above predictions was tested and confirmed in the present set of experiments. The effects of ondansetron, a potent and selective antagonist of the 5- HT3 receptor, were examined on (1) frequency of the hippocampal theta rhythm, (2) induction of LTP in field CA1 of freely moving rats, and (3) retention of olfactory and spatial memory in tasks known to depend on an intact hippocampus. When injected intraperitoneally into freely moving rats, the drug reliably and significantly increased the frequency of the hippocampal theta rhythm in a dose-dependent manner. Second, at concentrations that facilitate theta frequency (100 micrograms/kg and 500 micrograms/kg), an injection of the drug 30 min prior to delivering electrical stimulation bursts significantly increased the magnitude and duration of LTP compared to that obtained in the same animals after vehicle injections.(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of Intrinsic Circuits by Serotonin 5-HT3Receptors in Developing Ferret Visual Cortex

“…The involvement of 5-HT 3 receptors in these effects, however, has not yet been investigated. In the hippocampus, the 5-HT 3 receptor-mediated increase in GABAergic network activity (Kawa, 1994) leads to decreased excitability of pyramidal cells and reduced long-term potentiation induction (Staubli and Xu, 1995;Reznic and Staubli, 1997). Our results indicate the presence of similar mechanisms in the neocortex.…”

Serotonin 5-HT1A Receptors Modulate Hippocampal Reactivity to Afferent Stimulation

“…These cells express 5-H T3 receptors which, when activated, produce a transient depolarization and discharge of action potentials that hyperpolarizes dentate granular neurons (Ropert and Guy, 1991;Kawa, 1994;Piguet and Galvan, 1994). The 5-HT3 receptor has been shown to control DG activity, and its blockade by ondansetron enhances learning and long-term potentiation (Staubli and Xu, 1995). However, it is not likely that 5-HT3 receptors are the primary receptors to be involved in the present phenomena, because ondansetron, applied peripherally or centrally, did not affect FFA action.…”

Cellular Basis for Learning Impairment in Fragile X Syndrome

“…The discussion has emphasized cellular mechanisms and has omitted detailed consideration of the role of theta and bursting in learning and memory. A few studies have reported parallel effects of experimental manipulations on spontaneous theta rhythm in vivo and theta-burst LTP (Maren et al, 1994;Staubli and Xu, 1995). An alternative approach, showing that theta-burst stimulation in vivo produces synaptic potentiation as its behavioral significance is learned (Roman et al, 1987) was instrumental in the development of the theta-burst LTP paradigm.…”