Further Evidence for a Dissociation Between Different Forms of Mnemonic Expressions in a Mouse Model of Age-related Cognitive Decline: Effects of Tacrine and S 17092, a Novel Prolyl Endopeptidase Inhibitor

Abstract

It has been demonstrated previously on the radial maze that the emergence of an age-related mnemonic impairment is critically dependent on the form which the discrimination problems took. Hence, when the arms were presented one by one (i.e., successive go-no-go discrimination), both adult and aged mice learned to distinguish between positive (baited) and negative (unbaited) arms readily, as evidenced by their increased readiness to enter positive relative to negative arms (i.e., by a differential in arm-entry latencies). A selective impairment in the aged mice was seen when these arms were presented subsequently as pairs, such that the mice were confronted with an explicit choice (i.e., simultaneous 2-choice discrimination). When discriminative performance was measured by the differential run speed between positive and negative arms, aged mice were also impaired. This was particularly pronounced in the 2-choice discrimination condition. We examined the effects of tacrine (3mg/kg, subcutaneously) or S 17092 (10mg/kg, orally) in aged mice on the three behavioral indices of this 2-stage spatial discrimination paradigm. The results indicated that: (1) Tacrine, but not S 17092, enhanced the acquisition of go-no-go discrimination as reflected in arm-entry latencies; (2) both drugs improved choice accuracy in simultaneous discrimination, although the effect of tacrine was less striking and, in particular, far from statistical significance in the very first 2-choice responses; and (3) neither drugs significantly affected run-speed performance. We conclude further that the specific patterns of drug effects on the three indices of discriminative performance might suggest that each index is associated with a distinct form of mnemonic expression relying on separate neural systems.In humans, declarative/explicit memory appears to be more vulnerable to deterioration in senescence than procedural/ implicit memory (Poon 1985;Gabrieli 1996;Schugens et al. 1997). One cardinal characteristic of declarative memory is its flexibility as exemplified by its capacity to support inferential use of memories in novel situations (Cohen 1984). Using a two-stage paradigm of discrimination learning, Marighetto et al. (1999) have previously demonstrated that aged mice displayed impaired inferential abilities when they were required to make an explicit choice between two eventualities that were only encountered before separately, but never conjointly. In Stage 1, the mice learned to discriminate between the valence of three baited (positive) and three unbaited (negative) arms in a radial maze with each of the arms presented one at a time, i.e., successive go-no-go discrimination. Successful discrimination was indicated by the animals' increased readiness to enter positive arms relative to negative ones. In Stage 2, the animals were confronted with an explicit choice between one positive arm and one negative arm they had learned to discriminate previously. Aged mice, but not young ones, were unable to translate their preference for the positive ...

Alleviation of a Selective Age-Related Relational Memory Deficit in Mice by Pharmacologically Induced Normalization of Brain Retinoid Signaling

“…It follows that the deleterious effect of age, and its reversal by RA, must be cognitive in nature. These contrasting effects should be taken as further evidence that these two versions of the position discrimination (i.e., stage 1 and stage 2) rely on distinct and dissociable memory systems Marighetto et al, 1999Marighetto et al, , 2000. The go-no-go discrimination in stage 1 involves separate unitary responses to individual arms and therefore can be achieved using elemental stimulus-response associations, forms of procedural and/or implicit memory that are independent of the hippocampal system.…”

Retinoid Hyposignaling Contributes to Aging-Related Decline in Hippocampal Function in Short-Term/Working Memory Organization and Long-Term Declarative Memory Encoding in Mice

“…7 A, B, 8A, B). This specific loss of mnemonic flexibility, revealed by a test situation demanding an explicit comparison between separately acquired information, has been proposed as a mouse model for the preferential declarative memory loss in senescence (Marighetto et al, 1999(Marighetto et al, , 2000 and in association with hippocampal dysfunction (Etchamendy et al, 2001(Etchamendy et al, , 2003Touzani et al, 2003;Mingaud et al, 2007). The deficit selectivity enables us to rule out trivial explanations (such as deterioration in motivation, perception, and locomotion) for observed changes in behavior (and concomitant brain activity, see below) in the aged mice.…”

Peptidomics of the Prolyl Peptidases

“…The identification of these substrates led to new hypotheses about Prep function, which were tested in vivo using pharmacological Prep inhibitors. Interestingly, several of these experiments suggested that Prep inhibition would lead to improved cognitive function in mammals, which was later verified (15)(16)(17)(18). However, the underlying mechanism for this improvement is still under investigation because some of the Prep substrates predicted to be responsible for this effect were unaffected, or only modestly affected, upon Prep inhibition (19)(20)(21).…”

“…The unique biochemical activity of Prep, namely the ability to cleave peptides at proline amino acids, has prompted a great deal of research into the biochemical, cellular, and physiological functions of this protein (9). In vitro assays have identified Prep substrates that range from the tripeptide, thyrotropin-releasing hormone, to a 31 amino acid peptide, beta endorphin (9,34), which led to new hypotheses about the physiological role of Prep, including a role in cognitive function (15)(16)(17)(18).…”

“…Differences in ion abundance between the two samples revealed Prep-regulated peptides, including substrates and products of the enzyme. c The identification of natural substrates, such as Hspa12a (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23), revealed that Prep can show cleavage site selectivity between two proline amino acids, which would not have been predicted based on the known substrate selectivity of Prep. d Prep also showed a length dependence, preferring shorter substrates, which allows it to cleave the degradation fragment of CGRP, CGRP(20-37), without cleaving the bioactive species CGRP any proline in a peptide can be found in the in vivo data.…”