Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 32 (4), 698-706

The N-methyl-D-aspartate Receptor Modulator GLYX-13 Enhances Learning and Memory, in Young Adult and Learning Impaired Aging Rats

Affiliations

The N-methyl-D-aspartate Receptor Modulator GLYX-13 Enhances Learning and Memory, in Young Adult and Learning Impaired Aging Rats

Jeffrey Burgdorf et al. Neurobiol Aging.

Abstract

NMDA receptor (NMDAR) activity has been strongly implicated in both in vitro and in vivo learning models and the decline in cognitive function associated with aging and is linked to a decrease in NMDAR functional expression. GLYX-13 is a tetrapeptide (Thr-Pro-Pro-Thr) which acts as a NMDAR receptor partial agonist at the glycine site. GLYX-13 was administered to young adult (3 months old) and aged (27-32 months old) Fischer 344 X Brown Norway F1 rats (FBNF1), and behavioral learning tested in trace eye blink conditioning (tEBC), a movable platform version of the Morris water maze (MWM), and alternating t-maze tasks. GLYX-13 (1mg/kg, i.v.) enhanced learning in both young adult and aging animals for MWM and alternating t-maze, and increased tEBC in aging rats. We previously showed optimal enhancement of tEBC in young adult rats given GLYX-13 at the same dose. Of these learning tasks, the MWM showed the most robust age related deficit in learning. In the MWM, GLYX-13 enhancement of learning was greater in the old compared to the young adult animals. Examination of the induction of long-term potentiation (LTP) and depression (LTD) at Schaffer collateral-CA1 synapses in hippocampal slices showed that aged rats showed marked, selective impairment in the magnitude of LTP evoked by a sub-maximal tetanus, and that GLYX-13 significantly enhanced the magnitude of LTP in slices from both young adult and aged rats without affecting LTD. These data, combined with the observation that the GLYX-13 enhancement of learning was greater in old than in young adult animals, suggest that GLYX-13 may be a promising treatment for deficits in cognitive function associated with aging.

Figures

Fig. 1
Fig. 1. GLYX-13 enhanced learning in the tEBC paradigm in old rats
(A) Mean ± SEM percent adaptive conditioned responses (CRs) during trace eye blink conditioning in old (27–32 month) rats. GLYX-13 (1.0 mg/kg IV) or vehicle was administered 10 min before the start of habituation or testing. This enhancement persisted throughout the entire experiment. GLYX-13 produced a similar enhancement of learning in young adult rats (Moskal et al., 2005). B. The learning enhancement developed slowly during the first day of training. Old animals treated with GLYX-13 showed a significant increase in learning (as measured by adaptive CRs) compared to controls on blocks 3–6 of the first day of training (P < .05; Fisher's PLSD planned comparison), but not during the first two blocks of training.
Fig. 1
Fig. 1. GLYX-13 enhanced learning in the tEBC paradigm in old rats
(A) Mean ± SEM percent adaptive conditioned responses (CRs) during trace eye blink conditioning in old (27–32 month) rats. GLYX-13 (1.0 mg/kg IV) or vehicle was administered 10 min before the start of habituation or testing. This enhancement persisted throughout the entire experiment. GLYX-13 produced a similar enhancement of learning in young adult rats (Moskal et al., 2005). B. The learning enhancement developed slowly during the first day of training. Old animals treated with GLYX-13 showed a significant increase in learning (as measured by adaptive CRs) compared to controls on blocks 3–6 of the first day of training (P < .05; Fisher's PLSD planned comparison), but not during the first two blocks of training.
Fig. 2
Fig. 2. GLYX-13 enhanced learning in the Morris water maze in both young and old rats
Data are presented as the mean ± SEM path length to the hidden platform for each of the 7 test days in the movable platform version of this task. Young adult (3 months) or old (27–32 months) rats were given IV injections of GLYX-13 (1.0 mg/kg, I.V.) or vehicle 10 min before the start of testing. GLYX-13 enhanced learning and memory in both the young adult and old animals. GLYX-13 facilitated learning and memory to a greater extent in the old animals as indexed by both an Age × Drug interaction (P < .05), and a greater reduction in mean path length in drug vs. vehicle treated animals (P < .005). This may be due to a “floor effect” for the young animals (see Results for more detail).
Fig. 3
Fig. 3. GLYX-13 enhanced learning in the T-maze task in both young and old rats
Data are presented as the mean ± SEM trials to criterion (9 out of 10 consecutive correct choices on each testing day). Food deprived rats were rewarded for left arm choices on day 1 and right arm choices on day 2. Ten min before the start of each testing day, animals were given I.V. injections of 1.0 mg/kg of GLYX-13 or Vehicle. GLYX-13 significantly facilitated learning in both young adult and aging rats in both the non-alternating and alternating t-maze (P <.05).
Fig. 4
Fig. 4
1 μM GLYX-13 enhances magnitude of long-term potentiation (LTP), without affecting long-term depression (LTD), in slices from young adult (2 month old) Fischer 344 rats. (A) Time course of LTP induced by four high frequency theta burst stimulus trains (10×100Hz 5 pulse bursts 200 msec interburst interval; arrow) at Schaffer collateral-CA1 synapses in slices pre-treated with GLYX-13 (1 μM; solid bar; filled circles; n=12), compared to control, untreated slices (open circles; n=12). (Insets: sample field e.p.s.p.s before (1) and after (2) induction of LTP in a GLYX-13 treated (a) and Control (b) slices. (B) Time course of LTD induced by a low-frequency stimulus train (2Hz/10min; arrow) at Schaffer collateral-CA1 synapses in slices pre-treated with GLYX-13 (1 μM; solid bar; filled circles; n=9), compared to control, untreated slices (open circles; n=10). (Insets: sample field e.p.s.p.s before (1) and after (2) induction of LTD in a GLYX-13 treated (a) and Control (b) slices.
Fig. 5
Fig. 5
GLYX-13 produces a greater enhancement in Schaffer collateral-CA1 LTP, without altering LTD, in slices from aged (24 month old) Fischer 344 rats. (A) Time course of LTP induced by four high frequency theta burst stimulus trains (10×100Hz 5 pulse bursts 200 msec interburst interval; arrow) at Schaffer collateral-CA1 synapses in slices pre-treated with GLYX-13 (1 μM; solid bar; filled circles; n=12), compared to control, untreated slices (open circles; n=12). (Insets: sample field e.p.s.p.s before (1) and after (2) induction of LTP in a GLYX-13 treated (a) and Control (b) slices. (B) Time course of LTD induced by a low-frequency stimulus train (2Hz/10min; arrow) at Schaffer collateral-CA1 synapses in slices pre-treated with GLYX-13 (1 μM; solid bar; filled circles; n=9), compared to control, untreated slices (open circles; n=10). (Insets: sample field e.p.s.p.s before (1) and after (2) induction of LTD in a GLYX-13 treated (a) and Control (b) slice). GLYX-13 enhanced LTP to a greater extent in young adult as compared to old rats as indexed by an Age × Drug interaction (P < .05).

Similar articles

See all similar articles

Cited by 33 PubMed Central articles

See all "Cited by" articles

Publication types

Feedback