Role of voltage-dependent calcium channel long-term potentiation (LTP) and NMDA LTP in spatial memory

Abstract

This experiment explores the role of two forms of long-term potentiation (LTP) in behavioral memory. NMDA and/or voltage-dependent calcium channels (VDCCs) were antagonized pharmacologically at levels that block nmdaLTP and vdccLTP, respectively, in rats learning an eight-arm radial maze task. Animals were trained twice a day for 11 d under the systemic influence of MK-801, verapamil, both drugs, or saline. During acquisition, the mixed drug group displayed significantly more working memory errors and reference memory errors than all other groups. The mixed drug group was markedly impaired on the first daily trial but improved dramatically on their second daily trial. After a 7 d delay, saline and MK-801 animals maintained their predelay level of performance. The performance of the verapamil groups declined significantly over the delay. These results demonstrate that: (1) vdccLTP is necessary for the retention of information over a 7 d period, (2) the blockade of both forms of LTP prevents the retention of information over a 21 hr period, and (3) blockade of both forms of LTP does not prevent the storing of information over a short period of time (3 hr).

Fig. 1.

Baits eaten. Group average baits eaten per trial across shaping (days 1–6), acquisition (days 7–11), and retention (day 18). Trials were terminated after eating four baits or 10 min. Animals were given one of four treatments: mixed drug (blocked both vdccLTP and nmdaLTP with10 mg/kg verapamil and 0.1 mg/kg MK-801, respectively) (⋄), verapamil (blocked vdccLTP with10 mg/kg verapamil) (■), MK-801 (blocked nmdaLTP with 0.1 mg/kg MK-801) (▵), and saline (control; 0.9%) (×). Treatments were administered intraperitoneally 15–30 min before the first trial (trial 1) of each day. Error bars have been omitted for clarity.

Fig. 2.

WMEs across shaping, acquisition, and retention trials. Each point is the average number of WMEs recorded on the first and on the second trials of each day by the four treatment groups. During shaping, the animals are learning which arms are baited and consequently do not enter all of the arms in the allotted 10 min. Because a WME occurs only with repeat arm entries, this measure is low during early shaping trials. During acquisition, the number of WMEs remains relatively constant for all but the group receiving blockade of both forms of LTP (mixed drug group). The mixed drug group (nmdaLTP and vdccLTP blocked) displays a dramatic scalloping, showing high levels of WMEs on the first daily trial and more normal levels on the second daily trial, which occurred 3 hr later. In the retention test, only the group receiving verapamil (to block vdccLTP) showed significant forgetting. The scalloped performance of the mixed drug group was still seen during retention tests. Error bars have been omitted for clarity.

Fig. 3.

A, WMEs during acquisition. Only the group receiving blockade of both forms of LTP (mixed drug group) had elevated WMEs limited to the first daily trial (*p < 0.05), thus producing the scalloping effect seen in Figure 2. These results suggest that blockade of both forms of LTP does not prevent the storing of information over a short period of time (the 3 hr between trial 1 and trial 2), but that it disrupts storage over a 21 hr period (between the last daily trial and the first trial on the following day). B, WMEs at retention. Across the retention interval, significant increases in WMEs on trial 1 were only seen for the verapamil group (*p < 0.04). The mixed drug group showed a similar trend, but this difference was not significant. The saline and MK-801 groups retained their performance across the delay interval. These results suggest that vdccLTP is necessary for the retention of the rules supporting WM performance across a 7 d interval in this task.

Fig. 4.

RMEs across shaping, acquisition, and retention trials. Each point is the average number of RMEs recorded on the first and on the second trials of each day. RMEs declined overall across acquisition trials, with the saline and verapamil groups showing the fewest errors. The mixed drug group displayed more RMEs on the first daily trial as compared with the second trial throughout acquisition. Only the verapamil group showed a significantly increased number of RMEs at retention. Error bars have been omitted for clarity.

Fig. 5.

A, RMEs during acquisition. The elevated RMEs of the mixed drug group were limited to the first trial of the day (*p < 0.05). These results suggest that blocking both forms of LTP interferes with the retention of RM over a 21 hr period from day to day, but not with retention over the 3 hr between trial 1 and trial 2 within a day. B, RMEs at retention. Only the verapamil group significantly increased RMEs across the 7 d retention delay (*p < 0.001). Comparisons were made on data from trial 1.