Delay-dependent working memory impairment in young-adult and aged 5-HT1BKO mice as assessed in a radial-arm water maze

Abstract

Serotonin (5-HT) plays a modulatory role in mnemonic functions, especially by interacting with the cholinergic system. The 5-HT1B receptor is a key target of this interaction. The 5-HT1B receptor knockout mice were found previously to exhibit a facilitation in hippocampal-dependent spatial reference memory learning. In the present study, we submitted mice to a delayed spatial working memory task, allowing the introduction of various delays between an exposure trial and a test trial. The 5-HT1BKO and wild-type mice learned the task in a radial-arm water maze (returning to the most recent presented arm containing the escape platform), and exhibited a high level of performance at delays of 0 and 5 min. However, at the delay of 60 min, only 5-HT1BKO mice exhibited an impairment. At a delay of 90 min, all mice were impaired. Treatment by scopolamine (0.8 mg/kg) 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. The 22-month-old wild-type and knockout mice exhibited an impairment at short delays (5 and 15 min). The effect of the mutation affected both young-adult and aged mice at delays of 15, 30, and 60 min. Neurobiological data show that stimulation of the 5-HT1B receptor inhibits the release of acetylcholine in the hippocampus, but stimulates this in the frontal cortex. This dual function might, at least in part, explain the opposite effect of the mutation on reference memory (facilitation) and delay-dependent working memory (impairment). These results support the idea that cholinergic-serotonergic interactions play an important role in memory processes.

Figure 1

(A) Performance on test trials in basic learning (without delay, i.e., delay 0 min) of wild-type and 5-HT1BKO (KO) mice across days (day: average measure on two successive days; i.e., 6-trial blocks). The performance is evaluated by the mean (± SEM) value of the ratio, visit to target arm/total number of visits. (B) Performance of wild-type and 5-HT1BKO mice on test trials depending on the duration of the retention interval. Retention intervals were 0, 1, 5, 60, and 90 min. (C) Effects of scopolamine (Scopo) administration (0.8 mg/kg, i.p.) as compared with saline (Sal) on performance of wild-type and 5-HT1BKO mice on delayed retention intervals. Retention intervals were 5 and 60 min. The long-dashed horizontal lines represent the threshold level of performance above chance level; the short-dashed horizontal lines represent performance at chance level. (***) P < 0.0005; (**) P = 0.001.

Figure 2

Incomplete visits during training (Experiment 2, stage 1). The values are expressed in terms of mean (± SEM) number of incomplete visits per day (sum of the three daily trials). (3m) 3-months old; (22m) 22-months old; (*) P = 0.01.

Figure 3

Effects of aging on performance of wild-type and 5-HT1BKO mice on delayed retention intervals. Retention intervals were 0, 5, 15, 30, 60, and 90 min. (3m) 3-months old; (22m) 22-months old. (***) P < 0.0001; (**) P = 0.01; (*) P < 0.05.

Figure 4

(A) Spatial working memory task. Schematic representation of the protocol. The radial-arm water maze is composed of 8 arms (A–H) radiating from a central area. During an exposure trial (left, Exposure Trial, ET), only one arm is available and contains the platform (here, arm H = target arm). During a subsequent test trial (right, Test Trial, TT), three arms are available. The task for the mouse is to return to the target arm without visiting arms with no platform. A delay of variable duration may be introduced during the retention interval between the ET and the TT. (B) Schematic representation of the design used in Experiment 1. Experiment 1 consisted of three successive stages corresponding to basic training (days 1–22), delay effect (days 23–29), and effect of scopolamine (days 32–39). All mice are injected with saline and scopolamine in alternation (1 d saline, the next day scopolamine) before each daily trial (see text for further details).