Object recognition memory and BDNF expression are reduced in young TgCRND8 mice

Abstract

The TgCRND8 mouse model of Alzheimer's disease exhibits progressive cortical and hippocampal β-amyloid accumulation, resulting in plaque pathology and spatial memory impairment by 3 months of age. We tested whether TgCRND8 cognitive function is disrupted prior to the appearance of macroscopic plaques in an object recognition task. We found profound deficits in 8-week-old mice. Animals this age were not impaired on the Morris water maze task. TgCRND8 and littermate controls did not differ in their duration of object exploration or optokinetic responses. Thus, visual and motor dysfunction did not confound the phenotype. Object memory deficits point to the frontal cortex and hippocampus as early targets of functional disruption. Indeed, we observed altered levels of brain-derived neurotrophic factor (BDNF) messenger ribonucleic acid (mRNA) in these brain regions of preplaque TgCRND8 mice. Our findings suggest that object recognition provides an early index of cognitive impairment associated with amyloid exposure and reduced brain-derived neurotrophic factor expression in the TgCRND8 mouse.

Fig. 1

Object recognition memory assessed at preplaque and plaque ages. TgCRND8 mice exhibit no discernable memory impairment at 4 weeks (A), but a profound deficit in 3-hour object recognition memory by 8 weeks (B). By 6 – 8 months of age, TgCRND8 mice are impaired at delays of 5 minutes, 1 hour, and 3 hours following initial exposure to objects (C). Values are means ± standard error of the mean (SEM) of memory index (MI) scores, with n ≥ 10 for each genotype at each delay interval. *p < 0.01 by unpaired Student t test.

Fig. 2

Exploration of objects and visual function examined in preplaque mice at 8 –9 weeks of age. Time in seconds (s) spent exploring both left and right objects during the initial exposure period are compared (A). TgCRND8 mice (n = 16) and nontransgenic (non-Tg) mice (n = 19) did not differ in duration of object exploration (p > 0.05, unpaired Student t test). Visual function was assessed by examination of head-tracking behavior (B). Animals were placed on a stationary platform within a patterned surface drum. The speed of the drum rotation was varied stepwise. The maximal angular speed at which an optokinetic response was detected greater than 50% of the time was calculated (frequency of extinction; FE). The FE (cycle/second) was calculated by multiplying spatial frequency of the drum visual pattern with angular velocity. TgCRND8 mice (n = 7) were comparable to non-Tg mice (n = 10) in their FE scores (p > 0.05, Mann-Whitney U test). Values are means ± standard error of the mean (SEM).

Fig. 3

Spatial reference memory in the Morris water maze assessed in 8-week-old mice. TgCRND8 mice (n = 5) were indistinguishable from nontransgenic (non-Tg) littermates (n = 5) in terms of their (A) swim-path length, (B) escape latency, and (C) swim speed. Data are means ± standard error of the mean (SEM) of all trials performed on each test day and were evaluated by repeated measures analysis of variance (ANOVA) (p > 0.05).

Fig. 4

Hippocampal brain-derived neurotrophic factor (BDNF) messenger ribonucleic acid (mRNA) levels measured by absolute quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR). At 6 weeks of age (A), TgCRND8 mice (n = 5) had reduced BDNF mRNA levels in the hippocampus compared with nontransgenic (non-Tg) mice (n = 4). However at 9 weeks (B), there was no significant difference between TgCRND8 mice (n = 7) and non-Tg littermates (n = 9). By 6 – 8 months (C), hippocampal BDNF mRNA was reduced in TgCRND8 mice (n = 4) in comparison with littermate controls (n = 4). Data are expressed as a ratio of copies of BDNF mRNA/copies of β-actin mRNA. Values are means ± standard error of the mean (SEM). *p < 0.05 by unpaired Student t test.

Fig. 5

Cortical brain-derived neurotrophic factor (BDNF) messenger ribonucleic acid (mRNA) levels in preplaque mice. At 6 weeks of age (A), TgCRND8 mice (n = 6) and nontransgenic (non-Tg) littermates (n = 6) had equivalent levels of BDNF mRNA in the cortex. By 9 weeks of age (B), TgCRND8 mice (n = 7) had reduced BDNF expression compared with non-Tg mice (n = 10). Data are expressed as a ratio of copies of BDNF mRNA/copies of β-actin mRNA. Values are means ± standard error of the mean (SEM). *p < 0.05 by unpaired Student t test.