The hippocampus is required for encoding spatial information. Little is known however, about how different attributes of learning are related to different types of synaptic plasticity. Here, we investigated the association between long-term depression (LTD) and long-term potentiation, both cellular models for learning, and novelty exploration. We found that exploration of a new environment containing unfamiliar objects and͞or familiar objects in new locations facilitated LTD, whereas exploration of the new environment itself, in the absence of objects, impaired LTD. Furthermore, we found this phenomenon to be modulated by 5-hydroxytryptamine 4 receptor activation. In contrast, long-term potentiation was facilitated by exploration of an empty novel environment, but simultaneous object exploration caused depotentiation. We also found that no further LTD could be induced. These findings support a decisive role for LTD in the acquisition of object-place configuration and consolidate its candidacy as a learning mechanism. T he hippocampus is a key structure for formation of spatial memory (1). It has been proposed, however, that it may also contribute to certain forms of nonspatial memory (2, 3). While the debate continues, several investigations indicate that the hippocampus is involved in pairing configuration of stimuli, i.e., objects with location (4, 5). Furthermore, learning the sequential order of events requires an intact hippocampus (6); this corresponds to its proposed role in episodic memory in humans (7). In terms of recognition memory, a dissociation between hippocampus and the respective cortical area occurs (8); the perirhinal cortex encodes object recognition (9) and the piriform cortex encodes odor recognition (10). Although it may not contribute to the recognition of the distinct features characterizing stimuli, the hippocampus may act as a novelty detector, conducting mismatch predictions by comparing stored information with new incoming cues (11). The mechanism for encoding this type of information is as yet unidentified.Memory is achieved by experience-dependent changes in synaptic strength. These changes can take the form of persistent enhancements (long-term potentiation, or LTP), or long-term depressions (LTD), of synaptic transmission. It has been proposed that LTD, working together with LTP, underlies storage of memory (12). Whereas a certain number of studies have investigated the correlation between LTP and memory (13-15), very few investigations have addressed what possible role LTD may have in memory formation. Little is known about whether LTD plays an independent role, thus underlying certain distinctive types of information storage, or whether it merely enhances the signal-to-noise ratio or alternatively functions as the means to erase stored engrams (16). An association has been demonstrated between LTD and the acquisition of novel information (17). Whereas low-frequency stimulation during exploration of a novel holeboard, containing novel objects, resulted in LTD, LTD was not induci...

Homosynaptic long-term depression (LTD) consists of a persistent nonpathological decrease in synaptic transmission, which is induced by low-frequency stimulation. In vivo, low-frequency stimulation (1 Hz, 900 pulses) induces LTD in Wistar but not Hooded Lister rats. In this study, we investigated the inf luence of behavioral learning and behavioral state on the expression of LTD in both rat strains. Recordings were taken from freely moving animals that had undergone chronic implantation of a recording electrode in the hippocampal CA1 region and a bipolar stimulating electrode in the ipsilateral Schaffer collateral-commissural pathway. Exposure of the rat strains to stress induced a significant elevation in serum corticosterone levels but did not facilitate LTD expression. However, LFS given during exploration of a novel environment resulted in LTD expression in Hooded Lister, and LTD enhancement in Wistar, rats. Reexposure to the same environment did not result in new expression of LTD. Behavioral comparison between the first and second environmental exposure confirmed that the animals had habituated to the novel environment. These observations strongly implicate an association between novelty acquisition and LTD.It has been postulated that the mechanisms underlying longterm depression (LTD) expression in the cerebral cortex, together with the mechanisms of long-term potentiation (LTP), are responsible for information storage by the hippocampus (1). However, although extensive research has been conducted to establish whether LTP has a physiological basis in the mechanisms underlying learning events in the brain (2-6), very little attention has been paid to whether LTD also plays a role in such phenomena. LTD, rather, has been more widely considered as functioning simply to reverse LTP (7, 8), or alternatively as underlying physiological events that cause forgetting (9). Although homosynaptic LTD has been extensively described in vitro by means of electrophysiological recordings from hippocampal slices, its significance for memory processes has been questioned because of reported failures to induce persistent LTD in vivo (10, 11). On the other hand, LTD has been more recently reported in both anesthetized (12, 13) and freely moving rats (14). Thus, it may be that the conditions during which LTD is induced are critical for robust expression of this form of synaptic plasticity. Furthermore, LTD, when induced in freely moving rats, is persistent and endures for many days-an observation that indicates that synaptic information resulting from LTD induction can be retained long enough to contribute to a hippocampusdependent memory trace (1).In preliminary work, we observed that LTD expression induced by low-frequency stimulation (LFS) in the hippocampal CA1 region is strain dependent. This finding prompted the question whether rat strains that do not express LTD after LFS are simply LTD resistant or whether these rats are very sensitive to the induction conditions used. In the present study, we investigated thi...

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Hebbian learning models require that neurons are able to both strengthen and weaken their synaptic connections. Hippocampal synaptic plasticity, in the form of long-term potentiation (LTP) and long-term depression (LTD), has been implicated in both spatial memory formation as well as novelty acquisition. In addition, the ventral tegmental area-hippocampal loop has been proposed to control the entry of information into long-term memory, whereas the dopaminergic system is believed to play an important role in information acquisition and synaptic plasticity. D 1 /D 5 dopamine receptors are positively coupled to adenylyl cyclase and have been to modulate certain forms of synaptic plasticity, particularly in vitro. We investigated how D 1 /D 5 dopamine receptors modify long-lasting synaptic plasticity at CA1 synapses of adult freely moving rats and found that receptor activation lowered the threshold for the induction of both LTP and LTD. Specific types of learning are associated with specific types of hippocampal synaptic plasticity. We found that objectconfiguration learning, facilitation of late-phase LTD by object exploration, and late-phase LTP by exploration of empty space were all prevented by D 1 /D 5 receptor antagonism. Furthermore, receptor antagonism prevented electrically induced late-LTP, whereas receptor activation facilitated induction of both LTP and LTD by patterned electrical stimulation. These findings suggest that the dopaminergic system, acting via D 1 /D 5 receptors, gates long-term changes in synaptic strength and that these changes are a critical factor in the acquisition of novel information.

Novel spatial information is encoded in the hippocampus by plastic changes of synaptic properties. Novel space consists of several types of information that may evoke differential synaptic responses in individual hippocampal subregions. To examine this possibility, we recorded field potentials from the dentate gyrus (DG) and CA1 region in freely moving adult rats. Stimulation protocols that were marginally subthreshold for the induction of persistent long-term potentiation (LTP) or long-term depression (LTD) were implemented, concurrent with exposure to novel spatial information. We found that in both hippocampal subregions, exploration of a novel empty hole board facilitated LTP. However, LTD facilitation was subregion specific and dependent on the nature of the cues. In the CA1 region, partially concealed cues had a facilitatory effect on LTD. LTD in the DG was facilitated by large directional cues. Thus, although LTP was facilitated uniformly in both areas by the same novel environment, LTD was facilitated in a region-specific manner, based on the nature of the cue. This implies that spatial changes within an environment elicit local changes of synaptic weights dependent on the type of information and, hence, generate a complete cognitive map as a consequence of cooperation of synaptic plasticity in all participating subregions.

This study examined the role of metabotropic glutamate receptors (mGluRs) in hippocampal long-term depression (LTD) in vivo. The group 1 mGluR antagonist (S)4-carboxyphenylglycine (4CPG), group 1/2 antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG), and group 2 antagonists (RS)-alpha-methylserine-O-phos-phate monophenyl ester (MSOPPE) and (2S)-alpha-ethylglutamic acid (EGLU) were used. The NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (AP5) was used to examine the NMDA receptor contribution to the observed LTD. Adult male Wistar rats underwent implantation of stimulating and recording electrodes into the Schaffer collaterals and CA1 stratum radiatum, respectively. After recovery of 5-7 d, the field EPSP was measured from freely moving animals. Drugs were applied either before or after 1 Hz low-frequency train (LFT) or 100 Hz stimulation via a cannula implanted in the lateral cerebral ventricle. Nine hundred pulses at 1 Hz produced an LTD that was marked and long-lasting. This LTD was completely inhibited by pre-LFT application of AP5. MCPG inhibited LTD from 2 hr post-LFT. 4CPG partially impaired LTD. MSOPPE and EGLU completely blocked induction of LTD, although short-term depression remained intact. MSOPPE did not block long-term potentiation (LTP) induced by 100 Hz stimulation, whereas 4CPG produced a significant inhibition. When MSOPPE was present, LTD could not be induced either before or after LTP induction, whereas LTD could be induced in an identical protocol in vehicle-injected animals. These results suggest a differential role for mGluRs in NMDA receptor-dependent hippocampal LTD in vivo. Group 1 mGluRs may play a role in both LTD and LTP, whereas group 2 mGluRs may be critically involved only in LTD induction.

Interneurons are critical for proper neural network function and can activate Ca2+ signaling in astrocytes. However, the impact of the interneuron-astrocyte signaling into neuronal network operation remains unknown. Using the simplest hippocampal Astrocyte-Neuron network, i.e., GABAergic interneuron, pyramidal neuron, single CA3-CA1 glutamatergic synapse, and astrocytes, we found that interneuron-astrocyte signaling dynamically affected excitatory neurotransmission in an activity- and time-dependent manner, and determined the sign (inhibition vs potentiation) of the GABA-mediated effects. While synaptic inhibition was mediated by GABAA receptors, potentiation involved astrocyte GABAB receptors, astrocytic glutamate release, and presynaptic metabotropic glutamate receptors. Using conditional astrocyte-specific GABAB receptor (Gabbr1) knockout mice, we confirmed the glial source of the interneuron-induced potentiation, and demonstrated the involvement of astrocytes in hippocampal theta and gamma oscillations in vivo. Therefore, astrocytes decode interneuron activity and transform inhibitory into excitatory signals, contributing to the emergence of novel network properties resulting from the interneuron-astrocyte interplay.DOI: http://dx.doi.org/10.7554/eLife.20362.001