Spatial Learning in the 5-HT1B Receptor Knockout Mouse: Selective Facilitation/Impairment Depending on the Cognitive Demand

Abstract

Age-related memory decline is associated with a combined dysfunction of the cholinergic and serotonergic systems in the hippocampus and frontal cortex, in particular. The 5-HT1B receptor occupies strategic cellular and subcellular locations in these structures, where it plays a role in the modulation of ACh release. In an attempt to characterize the contribution of this receptor to memory functions, 5-HT1B receptor knockout (KO) mice were submitted to various behavioral paradigms carried out in the same experimental context (water maze), which were aimed at exposing mice to various levels of memory demand. 5-HT1BKO mice exhibited a facilitation in the acquisition of a hippocampal-dependent spatial reference memory task in the Morris water maze. This facilitation was selective of task difficulty, showing thus that the genetic inactivation of the 5-HT1B receptor is associated with facilitation when the complexity of the task is increased, and reveals a protective effect on age-related hippocampal-dependent memory decline. Young-adult and aged KO and wild-type (WT) mice were equally able to learn a delayed spatial matching-to-sample working memory task in a radial-arm water maze with short (0 or 5 min) delays. However, 5-HT1BKO mice, only, exhibited a selective memory impairment at intermediate and long (15, 30, and 60 min) delays. Treatment by scopolamine induced the same pattern of performance in wild type as did the mutation for short (5 min, no impairment) and long (60 min, impairment) delays. Taken together, these studies revealed a beneficial effect of the mutation on the acquisition of a spatial reference memory task, but a deleterious effect on a working memory task for long delays. This 5-HT1BKO mouse story highlights the problem of the potential existence of "global memory enhancers." Data from cognitive psychology, neuropsychology, and behavioral neuroscience no longer conceive memory as a unitary process (e.g., Cohen and Squire 1980;Cohen 1984;Graf and Schacter 1985;Kesner 1986;Tulving 1987). Based on neuropsychological studies in humans, different memory systems have been defined on the basis of (1) the cognitive operations that they enable and (2) the structures of the central nervous system that are implicated therein. In the declarative system, long-term memory ensures the consolidation of information for long-term retrieval or recognition, and short-term memory allows the maintenance of information during short periods of time to execute a particular action or sequential actions (Baddeley 1995). Studies in humans may not be directly applicable to rodents. However, there may be some homologies that experiments in rodents reveal. Hence, if the hippocampus is conceived as a key structure involved in long-term, especially spatial memory (O'Keefe and Nadel 1978), but also in working memory (Olton et al. 1979), the prefrontal cortex is also considered as a key structure to complete working memory tasks (Fuster 1989;Tulving 1991), especially those that are sensitive to interferences.In humans as well as...

Serotonin as a Modulator of Glutamate- and GABA-Mediated Neurotransmission: Implications in Physiological Functions and in Pathology

“…Activation of hippocampal 5-HT 1B receptors induces a memory impairment [18], anxiety and a strong behavioral inhibition [17]. In line with this, 5-HT 1B knockout mice when confronted with a novel environment showed a less anxious and more explorative behavior [17,112] and in the Morris water maze acquired a hippocampus-dependent spatial reference memory task more easily than wild-type littermates [19], suggesting that 5-HT 1B antagonists might be useful in the treatment of anxiety and improve hippocampus-dependent memory.…”

Lack of serotonin1B receptor expression leads to age-related motor dysfunction, early onset of brain molecular aging and reduced longevity

“…Total activity in the open field and the elevated plus maze (EPM) tests were not different from WT controls and declined similarly with age (Figure 1c and d). This early decline in motor behavior in Htr1b KO mice was not due to learning deficits, 44 as procedural learning curves were essentially parallel between genotypes (Figure 1e). Consistent with previous reports, 28 Htr1b KO mice displayed normal anxiety-like behavior in young adulthood (Supplementary Figure S1).…”

“…Moreover, other neurotransmitters systems interacting with 5HT 1B R and not investigated here may have played a role in the mutant phenotype. In particular, changes in cholinergic functions may have occurred, as suggested by Buhot et al, 44 in view of complex changes in memory functions in aging Htr1b KO mice. 44 The presence of an early deficit in motor behavior was consistent with the role of 5-HT 1B R in motor function.…”

“…In particular, changes in cholinergic functions may have occurred, as suggested by Buhot et al, 44 in view of complex changes in memory functions in aging Htr1b KO mice. 44 The presence of an early deficit in motor behavior was consistent with the role of 5-HT 1B R in motor function. 28 The distribution and functional contribution of 5-HT 1B R in the spinal cord and cerebellum are low, 67,68 whereas the nature of the phenotype indicated a deficit in complex motor behavior (rotarod and coat hanger tests), rather than a decrease in locomotor and/or muscle strength (total activity and rearing in open field and EPM; early occurrence rather than accelerated frailty).…”

Water maze swim path analysis based on tracking coordinates

“…It may be especially useful in behavioral screening of knockout mice, which are increasingly used in different research areas and tested in different behavioral paradigms. Particularly in this field of research, the reliability of behavioral measures is under debate and there is a high demand for reproducible behavioral testing (Buhot et al, 2003;Holmes, Wrenn, Harris, Thayer, & Crawley, 2002;Karl, Pabst, & von Hörsten, 2003). This may be provided by the present method, due to its independence from experimenter-specific assumptions and differences in test procedures, such as arena size.…”