The 5-HT₇ receptor is involved in allocentric spatial memory information processing

Abstract

The hippocampus has been implicated in aspects of spatial memory. Its ability to generate new neurons has been suggested to play a role in memory formation. Hippocampal serotonin (5-HT) neurotransmission has also been proposed as a contributor to memory processing. Studies have shown that the 5-HT₇ receptor is present in the hippocampus in relatively high abundance. Thus the aim of the present study was to investigate the possible role of the 5-HT₇ receptor in spatial memory using 5-HT₇ receptor-deficient mice (5-HT₇^−/−). A hippocampus-associated spatial memory deficit in 5-HT₇^−/− mice was demonstrated using a novel location/novel object test. A similar reduction in novel location exploration was observed in C57BL/6J mice treated with the selective 5-HT₇ receptor antagonist SB-269970. These findings prompted an extended analysis using the Barnes maze demonstrating that 5-HT₇^−/− mice were less efficient in accommodating to changes in spatial arrangement than 5-HT₇^+/+ mice. 5-HT₇^−/− mice had specific impairments in memory compilation required for resolving spatial tasks, which resulted in impaired allocentric spatial memory whereas egocentric spatial memory remained intact after the mice were forced to switch back from striatum-dependent egocentric to hippocampus-dependent allocentric memory. To further investigate the physiological bases underlining these behaviors we compared hippocampal neurogenesis in 5-HT₇^+/+ and 5-HT₇^−/− mice employing BrdU immunohistochemistry. The rate of cell proliferation in the dentate gyrus was identical in the two genotypes. From the current data we conclude that the 5-HT₇^−/− mice performed by remembering a simple sequence of actions that resulted in successfully locating a hidden target in a static environment.

Introduction

Neuropsychological studies have shown that several brain regions including the medial temporal lobe [1], the hippocampus [2], [3], the parietal cortex [4], [5], [6], and the striatum [7], [8], [9] are involved in spatial memory processing. Spatial memory is the ability to code, store and retrieve information about spatial layouts in the environment, thus enabling the learning of a path between two points or remembering the location of objects. Several, more or less independent, components of spatial memory have been identified. Thus, procedural spatial learning (route learning) can be distinguished from declarative spatial memory (object location memory) [10]. Declarative spatial memory can be further subdivided into memory of the position of objects or stimuli that is independent of the observer (allocentric spatial memory) and memory that is in relation to the observer (egocentric spatial memory) [11]. Specifically, the dorsal and lateral striatum is involved in processing egocentric memory [12], [13], [7], and the hippocampus on the other hand is involved in allocentric spatial memory processing [14].

In animal studies, it has been demonstrated that the hippocampus is critical for the formation of spatial and contextual fear memories [15]. Intact immediate memory and abnormally rapid loss of spatial memory has been observed in animals with damage limited to the hippocampus [16] whereas memories acquired prior to the lesions remained intact. In rodents, hippocampal damage leads to reduced performance in the Morris water maze when the animal is placed at different positions in the maze for each trial (allocentric memory) [14] but not when placed at the same initial starting point for each trial (egocentric memory) [17]. Furthermore, aversive stimuli, such as foot shock, known to induce anxiety, depression, and fear memory, have been shown to also alter activity-dependent hippocampal synaptic plasticity [18], [19], [20]. The role of hippocampal region in initial formation of memories and its relay to a final storage in other parts of the brain has also been described in humans [21], [22], [23], [24].

5-Hydroxytryptamine (serotonin, 5-HT) can alter synaptic plasticity as demonstrated in studies of long-term potentiation (LTP) and depression (LTD) [25], [26]. Thus, it is possible that perturbations of 5-HT neurotransmission might affect hippocampus-dependent learning and memory. 5-HT exerts its action by interacting with at least 14 different receptor subtypes [27]. The 5-HT₇ receptor is one of the most recently discovered 5-HT receptors. It is a G protein-coupled receptor positively coupled to adenylyl cyclase. The highest density of 5-HT₇ receptor expression has been described in the thalamus, hippocampus, and frontal cortex [28], [29], [30]. A role for the 5-HT₇ receptor has been suggested in several physiological and pathophysiological phenomena, including memory formation and/or consolidation, depression, obsessive–compulsive disorder, circadian rhythm regulation, and sleep disorders [31]. Interestingly, it has been shown that mice lacking the 5-HT₇ receptor show a selective impairment in contextual fear conditioning [32]. Furthermore, there was a reduced ability to induce LTP in hippocampal slices from these mice [32]. These findings suggest a role of the 5-HT₇ receptor in hippocampal function. Additionally, selective 5-HT₇ receptor antagonist SB-269970 influences hippocampus-dependent learning [33].

A unique feature of the hippocampus is its ability to generate new neurons even in adulthood. It has been shown that the newly born neurons become synaptically active [34]. Based on these and other studies [35], [36], a putative link between adult neurogenesis and hippocampal functions have been made, especially a link with learning and memory [37].

In order to further study the possible involvement of 5-HT₇ receptors in hippocampal function we have employed behavioral models to assess hippocampus-dependent learning and memory, and investigated hippocampal neurogenesis in 5-HT₇ receptor-deficient mice. It was hypothesized that pharmacological blockage or inactivation of 5-HT₇ receptor might result in impairments in the ability of mice to correctly integrate and/or utilize information regarding their environment resulting in difficulties to cope with spatial changes.