Artificially induced synaptic plasticity has many forms, some of which may mimic naturally occurring processes more closely than others. The sensitivity of electrically induced synaptic plasticity to behavioural conditions provides a powerful means of determining how well they model naturally occurring synaptic plasticity. Recently we have examined the role of aminergic inputs to the intact hippocampus in mediating/modulating the effects of exposure to non-stressful and stressful environments on LTP induction in the CA1 area of the rat. In particular, exposure to a non-stressful novel environment facilitated the induction of LTP via increased dopaminergic transmission (Li et al. 2003). In contrast, exposure to an inescapable stressful environment blocked the induction of LTP in a manner dependent on endogenous serotonergic tone (Shakesby et al. 2002).

Unpredicted information that triggers exploration may be of future adaptive significance and may thus gain preferential status for memory encoding. As the rodent hippocampus is particularly tuned to spatial information storage we hypothesized that if LTP-like mechanisms are involved in encoding for memory then exposure to a novel environment that triggered exploration should facilitate LTP induction. We found that freely behaving animals that explored a novel environment for the first time had a reduced threshold for LTP induction. The facilitation of LTP was observed in a narrow time window (brief novelty exposure introduced 5 min after, but not 5 min before, conditioning stimulation). Furthermore, the facilitation of LTP induction by the novel environment was dependent on endogenous dopaminergic tone. Thus, block of D1/D5 receptors with the antagonist SCH23390 prevented the facilitation of LTP by novelty in awake animals. In contrast the β-adrenoceptor antagonist propranolol and the muscarinic cholinoceptor antagonist scopoloamine were without effect. Furthermore, activation of D1/D5 receptors with the agonist SKF38393 in anaesthetized animals was sufficient to facilitate LTP induction. This effect was blocked by the membrane-permeant PKA inhibitor Rp-cAMPS. These results strongly implicate a requirement for dopamine-dependent LTP-like synaptic plasticity in hippocampal memory formation.

Stress has been reported to either facilitate or block the acquisition, consolidation and/or recall of hippocampal-dependent learning tasks depending on experimental conditions (Diamond D, this symposium). Exposure to an inescapable stressful environment that causes behavioural ‘freezing’ dramatically affects synaptic plasticity, blocking LTP induction and facilitating LTD induction (Xu et al. 1997). A wide variety of neurotransmitter and neuroendocrine systems are activated by stress that can potentially affect synaptic plasticity. Recently we have examined serotonergic mechanisms in maintaining, or overcoming, the block of LTP induction. We investigated the effects of agents that regulate endogenous 5-HT on the ability of conditioning stimulation to induce LTP in anaesthetised animals that had been placed on an inescapable elevated platform for 30 min. Tianeptine, an antidepressant agent that lowers endogenous 5-HT levels, given after the stress reversed the block of LTP induction. In non-stressed animals the stress-evoked block of LTP was mimicked by fluoxetine and fenfluramine, agents that increase extracellular 5-HT concentration. Remarkably, raising 5-HT levels with fenfluramine in stressed animals also overcame the block of LTP induction, probably by activation of 5-HT2 receptors (see B. Ryan et al. this meeting). These results point to a possible key role of endogenous 5-HT in mediating and overcoming the effects of inescapable stress on plasticity at glutamatergic synapses.

Exposure to a novel environment that initiates either approach or aversion has dramatic and opposite effects on the induction of LTP in the intact hippocampus. The sensitive regulation by aminergic mechanisms points to a key role for these extra-hippocampal influences on naturally occurring synaptic plasticity.

This work was supported by Science Foundation Ireland, Irish Higher Education Authority, Irish Research Council for Science, Engineering and Technology, the Wellcome Trust and the Irish Health Research Board. We also wish to thank W. Cullen, S. Li, A. Shakesby and L. Xu for their contributions.