Intermediate- and long-term recognition memory deficits in Tg2576 mice are reversed with acute calcineurin inhibition

Abstract

The Tg2576 transgenic mouse is an extensively characterized animal model for Alzheimer's disease (AD). Similar to AD, these mice suffer from progressive decline in several forms of declarative memory including contextual fear conditioning and novel object recognition (NOR). Recent work on this and other AD animal models suggests that initial cognitive deficits are due to synaptic dysfunction that, with the correct intervention, are fully treatable. We recently reported that acute calcineurin (CaN) inhibition with FK506 ameliorates one form of declarative memory (contextual fear conditioning) impairment in 5 months old Tg2576.This study tested whether acute CaN inhibition rescues deficits in an additional form of declarative memory, spontaneous object recognition, by employing the NOR paradigm. Furthermore, we determined whether FK506 rescue of NOR deficits depends on the retention interval employed and therefore is restricted to short-term, intermediate-term, or long-term memory (STM, ITM or LTM, respectively). In object recognition, Tg2576 are unimpaired when NOR is tested as a STM task and CaN inhibition with FK506 does not influence NOR STM performance in Tg2576 or WT mice. Tg2576 were impaired in NOR compared to WT mice when a 4 or 24 hour retention interval was employed to model ITM and LTM, respectively. Acute CaN inhibition prior to and during the training session reversed these deficits in Tg2576 mice with no effect on WT performance. Our findings demonstrate that aberrant CaN activity mediates object recognition deficits in 5 months old Tg2576 when NOR is employed as a test for ITM and LTM. In human AD, CaN inhibition may lead the way for therapeutics to improve declarative memory performance as demonstrated in a mouse model for AD.

Early Impairment of Long-Term Depression in the Perirhinal Cortex of a Mouse Model of Alzheimer's Disease

“…The impairment in LTD is consistent with visual recognition deficits observed in these mice at 5 months of age 9 and in AD patients in the very early phase of the disease, 13 as LTD in the Prh is believed to underlie this form of memory. 11,12 On the other hand, the impairment in LTD may appear to be in contrast with previous reports in AD models showing enhancement of LTD and inhibition of LTP.…”

“…Interestingly, a significant impairment in synaptic transmission was also observed at 1-4 months, whereas LTP was unaffected at 8-10 months. 20 In conclusion, these results suggest that synaptic transmission and LTD induction in the Prh are particularly sensitive to early AD pathogenic events, in accordance with early deficits in visual recognition memory in the same AD model 9 and in AD patients. 13 Further investigation is needed to characterize the mechanisms underlying the observed synaptic deficits.…”

Pterostilbene ameliorates intracerebroventricular streptozotocin induced memory decline in rats

“…Ability to discriminate represents intact learning and memory function. Increase in RI in NORT demonstrates proper learning and memory function (Karasawa et al 2008;Taglialatela et al 2009;Greco et al 2010;Zhanga et al 2012). Positive control rats showed fall in RI while treatment with PTS and FF lead to increase in RI.…”

Recognition memory in tree shrew (Tupaia belangeri) after repeated familiarization sessions

“…By contrast, rodents do not provide a good model for assessing detrimental effects on LTM. Nevertheless, to date, almost all NOR tests have been done in rodents and this test is increasingly used in rodent animal models of various diseases including Alzheimer's Disease (Donkin et al, 2010;Greco et al, 2010;Hillen et al, 2010;Lu et al, 2009;Mouri et al, 2007;Nishida et al, 2006;Taglialatela et al, 2009), schizophrenia (Hauser et al, 2009;McLean et al, 2009;Neill et al, 2010;Ozawa et al, 2006;Powell et al, 2007;Vigano et al, 2009), and Down's syndrome (Lockrow et al, 2010). The absence of any external reinforcement in the NOR test is particularly important as it makes it more comparable to memory tests in human, which are normally conducted without the use of positive or negative reinforcers such as food and electric shock (Ennaceur and Delacour, 1988).…”