Hippocampal long-term depression mediates spatial reversal learning in the Morris water maze

Abstract

Synaptic plasticity at hippocampal excitatory synapses has been proposed as the cellular mechanism underlying spatial learning and memory. However, most previous studies have focused on the role of long-term potentiation (LTP) in learning and memory, and much less is known about the role of long-term depression (LTD). Here, we report that hippocampal-dependent spatial learning in the Morris water maze facilitated hippocampal CA1 LTD induction in vivo. The LTD can be blocked by systemic application of the selective GluN2B antagonist Ro25-6981 (6 mg/kg, i.p.) or a synthetic peptide Tat-GluA2_3Y (3 μmol/kg, i.p.) that interferes with the endocytosis of AMPA receptors. In addition, systemic or intrahippocampal administration of these two mechanistically and structurally distinct inhibitors impaired spatial reversal learning of a novel target location, when the hidden platform was moved to the quadrant opposite the initial target location. Notably, acute elevated-platform stress, which facilitates hippocampal LTD induction, enhanced both acquisition and retrieval of spatial reversal memory. The present study demonstrates that reversal learning is impaired by blocking hippocampal LTD, and enhanced by facilitating hippocampal LTD, suggesting that hippocampal LTD may be necessary and sufficient to mediate new information processing.

This article is part of a Special Issue entitled ‘Cognitive Enhancers’.

Introduction

It is widely held that the cellular mechanism underlying learning and memory in the brain is activity-dependent synaptic plasticity, e.g., N-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) and long-term depression (LTD) (Bliss and Collingridge, 1993; Collingridge et al., 2010; Malenka and Nicoll, 1999; Martin et al., 2000). Behavioral experience may generate endogenous synaptic plasticity to dynamically modulate the induction threshold for subsequent hippocampal LTP and LTD (Kemp and Manahan-Vaughan, 2004; Manahan-Vaughan and Braunewell, 1999). However, most previous experiments have focused on the potential role of LTP in learning and memory (Lynch, 2004; Malenka and Nicoll, 1999; Martin et al., 2000). Correlations between behavioral experience and LTD modulation have not been extensively investigated. Early speculation that LTD may serve as a reversal mechanism for LTP, or a forgetting mechanism, assumed that LTP encodes memories (Stanton, 1996; Tsumoto, 1993). However, recent reports also indicate that LTD plays important roles in processing new information. For example, hippocampal LTD is facilitated by exposure to a novel environment with novel objects or novel configuration of objects (Kemp and Manahan-Vaughan, 2004; Manahan-Vaughan and Braunewell, 1999) and we have recently found that induction of hippocampal CA1 LTD promotes the consolidation of spatial learning in freely moving rats (Ge et al., 2010).

The exact mechanisms underlying the involvement of hippocampal LTD in learning and memory are still not clear, partially due to the difficulty of inducing LTD with classical low frequency stimulation (LFS) protocols in adult animals (Staubli and Scafidi, 1997; Wong et al., 2007; Xu et al., 1998b). To better understand the role of hippocampal LTD in learning and memory, it is necessary to use a behavioral model in which experience may decrease the induction threshold of hippocampal LTD so that the subsequent classical LFS induces LTD. Several groups have recently investigated the potential role of hippocampal LTD in spatial reversal learning in the Morris water maze. Reversal learning occurs following initial spatial learning by changing the location of hidden platform in water maze. A recent report shows that exogenous d-serine enhances GluN2B-dependent LTD as well as reversal learning in mice, although it has no effect on normal water maze memory acquisition (Duffy et al., 2008). Another report shows that transgenic mice lacking NMDAR-dependent LTD display normal spatial learning ability, but exhibit both delayed acquisition of reversal learning and perseveration for the previous location during reversal learning in the water maze (Nicholls et al., 2008). Although these results suggest that NMDAR-dependent LTD may be involved in spatial reversal learning, it has been difficult to obtain a direct causal link between hippocampal LTD and spatial reversal learning. Thus, the use of specific LTD inhibitors to examine the precise contribution of hippocampal LTD in spatial reversal learning is necessary.

In the present study, we use two mechanistically and structurally distinct LTD inhibitors to investigate the role of hippocampal LTD in reversal learning with a combination of electrophysiological and behavioral assessments. We found initial spatial learning in the water maze facilitates hippocampal CA1 LTD induced by classical LFS, which can be blocked by systemic administration of Ro25-6981 and Tat-GluA2_3Y peptide. Furthermore, spatial reversal learning is impaired by Ro25-6981 and Tat-GluA2_3Y peptide, and enhanced by facilitating hippocampal CA1 LTD with acute stress. These results suggest that hippocampal CA1 LTD is critical for spatial reversal learning.