5-HT1a receptor antagonists block perforant path-dentate LTP induced in novel, but not familiar, environments

Abstract

Numerous studies suggest roles for monoamines in modulating long-term potentiation (LTP). Previously, we reported that both induction and maintenance of perforant path-dentate gyrus LTP is enhanced when induced while animals explore novel environments. Here we investigate the contribution of serotonin and 5-HT1a receptors to the novelty-mediated enhancement of LTP. In freely moving animals, systemic administration of the selective 5-HT1a antagonist WAY-100635 (WAY) attenuated LTP in a dose-dependent manner when LTP was induced while animals explored novel cages. In contrast, LTP was completely unaffected by WAY when induced in familiar environments. LTP was also blocked in anesthetized animals by direct application of WAY to the dentate gyrus, but not to the median raphe nucleus (MRN), suggesting the effect of systemic WAY is mediated by a block of dentate 5-HT1a receptors. Paradoxically, systemic administration of the 5-HT1a agonist 8-OH-DPAT also attenuated LTP. This attenuation was mimicked in anesthetized animals following application of 8-OH-DPAT to the MRN, but not the dentate gyrus. In addition, application of a 5-HT1a agonist to the dentate gyrus reduced somatic GABAergic inhibition. Because serotonergic projections from the MRN terminate on dentate inhibitory interneurons, these data suggest 5-HT1a receptors contribute to LTP induction via inhibition of GABAergic interneurons. Moreover, activation of raphe 5-HT1a autoreceptors, which inhibits serotonin release, attenuated LTP induction even in familiar environments. This suggests that serotonin normally contributes to dentate LTP induction in a variety of behavioral states. Together, these data suggest that serotonin and dentate 5-HT1a receptors play a permissive role in dentate LTP induction, particularly in novel conditions, and presumably, during the encoding of novel, hippocampus-relevant information.Long-term potentiation (LTP) remains the most intensively studied model of the cellular mechanisms of synaptic plasticity that may underlie memory (Bliss and Lomo 1973;Bliss and Collingridge 1993). Previously, we and others reported that the magnitude and longevity of LTP is enhanced when LTP is induced while animals explore novel environments, suggesting that behavioral states that involve novelty, and presumably learning, are optimal for synaptic plasticity (Davis and Derrick 1997;Straube et al. 2003a;Davis et al. 2004; Kemp and ManahanVaughan 2004). In line with this finding, it is suggested that novelty engages the hippocampal formation in a distinct "mode" of operation that appears optimal for inducing synaptic plasticity, and presumably, encoding (Buzsaki 1989;Paulsen and Moser 1998;Vinogradova 2001;Hasselmo et al. 2002;Lisman and Otmakhova 2002;Davis et al. 2004;Guzowski et al. 2004).A number of studies suggest that the enhancement of LTP by novelty is mediated by monoaminergic neuromodulators (Bramham et al. 1997;Paulsen and Moser 1998;Li et al. 2003; Straube et al. 2005b). Previous studies strongly support roles for both norepinephrine (Kitchi...

High dose of 8-OH-DPAT decreases maximal dentate gyrus activation and facilitates granular cell plasticity in vivo

“…Moreover, we confirmed the lack of effect of lower doses of 8-OH-DPAt on the slope of the fEPSPs when systemically applied (Levkovitz and Segal 1997). However, it has to be noted that local application of 10 nmol of 8-OH-DPAt in DG produced a reduction of about 50 % in the slope 30 min after its application and a biphasical effect of pSpike amplitudes with a long-lasting decrease (Sanberg et al 2006). Under our conditions, since that synaptic excitability is only slightly diminished in rats treated with a high dose of the drug, the likelihood that a cell will generate an action potential from a given synaptic drive remained unchanged (Fig.…”

“…In a previous in vivo study, intra hippocampal application of 8-OH-DPAt abolishes inhibition of the population spike observed in the second evoked response at intervals of 30-100 ms (Sanberg et al 2006). In the present study, however, we observed different changes in paired-pulse relationships induced by its systemic administration.…”

“…A possible explanation of our lower effects on population response is probably due to the fact that the high dose of 8-OH-DPAt produces a mixed activation of pre-and postsynaptic 5-Ht 1A Rs while low doses are selectively acting on the autoreceptors within the raphe neurons (Klancnik et al 1989). Consistently, 8-OH-DPAt induced inhibition of population responses in a dose-dependent manner in the DG in vitro (Klancnik et al 1991) or when locally applied in the DG (Sanberg et al 2006). Moreover, it is possible that high dose 8-OH-DPAt effects are mediated by the coactivation of 5-Ht 7 Rs, as recently results indicate this R subtype has a role in memory and hippocampal plasticity (Hedlund and Sutcliffe 2004;Costa et al 2012a).…”

“…Consistently, 5-Ht 1A Rs in the DG exert an excitatory effect that plays a permissive role in long-term potentiation (LtP) induction, particularly in environments with a high degree of novelty (Sanberg et al 2006). Opposite results on DG excitability have been obtained with systemic administration of low doses of (+)-8-hydroxy-2-(di-N-propylamino) tetralin (8-OHDPAt) (Klancnik et al 1989;Sanberg et al 2006), a mixed 5-Ht 1A/7 agonist, likely due to the preferential activation of the somatodendritic 5-Ht 1A Rs in the raphe versus the post-synaptic 5-Ht 1A Rs that would result in hippocampal 5-Ht release decrease (Sharp and Hjorth 1990;Lacivita et al 2008). nevertheless, the involvement of 5-Ht 7 Rs in PP-DG synapse cannot be ruled out, considering new evidence of their involvement in CA3-CA1 hippocampal plasticity (Costa et al 2012a, b).…”

“…Earlier in vivo studies reported that 5-Ht releasers facilitate the response of dentate granule (DG) cells to perforant path (PP) stimulation (Richter-Levin and Segal 1990), an effect that is thought to be mediated by hippocampal post-synaptic 5-Ht 1A Rs (Levkovitz and Segal 1997) on GABAergic interneurons and consequent inhibition of GABA release (Freund et al 1990;Freund 1992;Gulyas et al 1999). Consistently, 5-Ht 1A Rs in the DG exert an excitatory effect that plays a permissive role in long-term potentiation (LtP) induction, particularly in environments with a high degree of novelty (Sanberg et al 2006). Opposite results on DG excitability have been obtained with systemic administration of low doses of (+)-8-hydroxy-2-(di-N-propylamino) tetralin (8-OHDPAt) (Klancnik et al 1989;Sanberg et al 2006), a mixed 5-Ht 1A/7 agonist, likely due to the preferential activation of the somatodendritic 5-Ht 1A Rs in the raphe versus the post-synaptic 5-Ht 1A Rs that would result in hippocampal 5-Ht release decrease (Sharp and Hjorth 1990;Lacivita et al 2008).…”