Suprachiasmatic lesions restore object recognition in down syndrome model mice

Abstract

The Ts65Dn mouse is a well-studied model of trisomy 21, Down syndrome. This mouse strain has severe learning disability as measured by several rodent learning tests that depend on hippocampal spatial memory function. Hippocampal long-term potentiation (LTP) is deficient in these mice. Short-term daily treatment with low-dose GABA receptor antagonists rescue spatial learning and LTP in Ts65Dn mice leading to the hypothesis that the learning disability is due to GABAergic over-inhibition of hippocampal circuits. The fact that the GABA receptor antagonists were only effective if delivered during the daily light phase suggested that the source of the excess GABA was controlled directly or indirectly by the circadian system. The central circadian pacemaker of mammals is the suprachiasmatic nucleus (SCN), which is largely a GABAergic nucleus. In this study we investigated whether elimination of the SCN in Ts65Dn mice would restore their ability to form recognition memories as tested by the novel object recognition (NOR) task. Full, but not partial lesions of the SCN of Ts65Dn mice normalized their ability to perform on the NOR test. These results suggest that the circadian system modulates neuroplasticity over the time frame involved in the process of consolidation of recognition memories.

Keywords: Circadian rhythms; Novel object recognition; Recognition memory; Ts65Dn mice.

Fig. 1

Tissue sections from mice with complete (CL) or partial lesions (PL) of the SCN, and from an unlesioned intact animal (Intact). The SCN is indicated by the arrow. Optic chiasm (OC) is shown for reference.

Fig. 2

(A) Profile of activity and (B) learning indices (LI) as well as exploration time and distance travelled during the Novel Object Recognition (NOR) for the 2N and the Ts65Dn (Ts) mice at baseline. Both 2N and Ts65Dn mice showed a light/dark activity pattern but the Ts65Dn mice are more active (*, p < 0.05). For the NOR, the training was done during day 1 (D1) and the testing during day 2 (D2). Data are plotted as box and whisker plots with median values and percentiles at 10 and 90%. Circles show data points for individual animals. Ts65Dn mice have memory impairment at baseline (*, p < 0.05) and travelled significantly more distance during the NOR testing than 2N (*, p < 0.05).

Fig. 3

Profile of activity of the 2N and Ts65Dn (Ts) mice that were arrhythmic (Arr) after surgery. (A) Example of actogram before the lesion (left) and after (right). The lesion led to a loss of rhythmicity. (B) Activity of 2N and Ts65Dn mice that were arrhythmic (Arr) or not (Rhy) after surgery (*, p < 0.05). A 24 h. pattern of activity is present only for rhythmic mice. Only the Ts65Dn mice showed significantly less activity after the lesion (*, p < 0.05).

Fig. 4

(A) Learning Index (LI) scores in the NOR test for 2N controls (left) and for Ts65Dn (Ts, right) mice. Data are plotted as box and whisker plots with median values and percentiles at 10 and 90%. Circles show data points for individual animals. Scores are plotted for the training phase on day 1 (D1) and for the testing phase on day 2 (D2) for animals in which the SCN was intact, partially lesioned (PL), or completely lesioned (CL). The exploration times (B) and the total distance (C) travelled by mice during the NOR training (D1) and testing phase (D2) for 2N controls (left) and Ts65Dn mice (Ts, right) depending of the lesion of animals: SCN intact, partially lesioned (PL), or completely lesioned (CL; *p < 0.05).