Memory and long-term potentiation (LTP) dissociated: normal spatial memory despite CA1 LTP elimination with Kv1.4 antisense - PubMed (original) (raw)

Memory and long-term potentiation (LTP) dissociated: normal spatial memory despite CA1 LTP elimination with Kv1.4 antisense

N Meiri et al. Proc Natl Acad Sci U S A. 1998.

Abstract

Long-term potentiation (LTP) in the hippocampal slice preparation has been proposed as an in vitro model for long-term memory. However, correlation of LTP with memory in living animals has been difficult to demonstrate. Furthermore, in the last few years evidence has accumulated that dissociate the two. Because potassium channels might determine the weight of synapses in networks, we studied the role of Kv1.4, a presynaptic A-type voltage-dependent K+ channel, in both memory and LTP. Reverse transcription-PCR and Western blot analysis with specific antibodies showed that antisense oligodeoxyribonucleotide to Kv1.4 microinjected intraventricularly into rat brains obstructed hippocampal Kv1.4 mRNA, "knocking down" the protein in the hippocampus. This antisense knockdown had no effect on rat spatial maze learning, memory, or exploratory behavior, but eliminated both early- and late-phase LTP and reduced paired-pulse facilitation (a presynaptic effect) in CA1 pyramidal neurons without affecting dentate gyrus LTP. This presynaptic Kv1.4 knockdown together with previous postsynaptic Kv1.1 knockdown demonstrates that CA1 LTP is neither necessary nor sufficient for rat spatial memory.

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Figures

Figure 1

Figure 1

(A) ODN analysis of Kv1.4 mRNA by RT-PCR. mRNA amplification from hippocampi of nine rats injected for 4 days with either sham, sense, or antisense to Kv1.4. (A1) Kv1.1; (A2) PGK1; (A3) Kv1.4. (B) Time chart of antisense microinjection performed every 24 hr as indicated by arrows on top line. Time chart for LTP (second line) measured after either 4 or 8 days of microinjection. Rats sacrificed for RT-PCR and Western blots after 4 or 8 days (third line). Water maze training on each of 4 consecutive days between the fourth and eighth days (fourth line). Quadrant analysis was performed on the 10th day, 2 days after the last training day.

Figure 2

Figure 2

Effect of antisense on rat spatial memory. (A) ODNs were injected every 24 hr for 4 days before the first training day. Injections were continued during training every day. Rats were given three training trails each day for 4 consecutive days each trial lasting up to 120 s. Escape latency was measured by using a stopwatch. (B) Two days after training the island was removed, and the search strategy of the rat was monitored to determine whether the rat searched for the island in the quadrant where the island was located previously. (C) Distance of swimming in the first encounter with the pool. (D) Open-field exploratory behavior was monitored 1 day after the quadrant analysis in the same pool as the water maze but without water. All data are shown as means ± SEM.

Figure 3

Figure 3

LTP was eliminated and PPF was reduced in CA1 pyramidal neurons from Kv1.4 antisense-treated animals. (A) Lack of LTP in CA1 pyramidal neurons from the antisense-treated rats, showing an example of EPSPs (A1) evoked with single-pulse stimulation of the Schaffer collateral pathway (at arrow) and plotted group data (A2). Arrowhead in A1 points to a trace obtained 60 min after the tetanization, whereas the other trace was obtained 5 min before the tetanization. In A2, the arrow indicates the time of tetanization. (B) A tetanic train (arrow in B2) induced LTP in CA1 pyramidal neurons from sense-treated rats. The EPSP observed 60 min after tetanization (indicated by the arrowhead in B1) was potentiated as compared with that 5 min before tetanization (the unmarked trace in B1). (C) L-LTP was not induced in the antisense-treated group. Sample trace (indicated by the arrowhead in (C1) obtained with single-pulse stimulation of the Schaffer collateral pathway 70 min after the last train did not differ from the other trace obtained 5 min before the first train of stimulation. The tetanic trains induced a smaller and short-lasting posttetanic potentiation but the potentiation was not maintained (C2). (D) L-LTP was induced in the sense-treated group. For clarity, only every other data point is shown. (Inset) Traces were obtained 5 min before the first train (Control EPSP) and 4 hr after the last train (LTP). (E) PPF was largely inhibited in neurons from antisense-treated rats (E1) as compared with that from sense-treated rats (E2). The difference was significant (E3) at inter-stimulus intervals of either 30 or 50 ms (P < 0.05, unpaired t test). Plotted data are shown as means + SEM. (F) Western blot analysis of homogenate from six rats injected with either sense or antisense (F1) Kv1.4 (F2) _N_-methyl-

d

-aspartic acid-NR1.

Figure 4

Figure 4

LTP was induced in dentate granule neurons from Kv1.4 antisense-treated (A) and sense-treated (B) rats, shown as EPSPs (A1 and B1) evoked with single-pulse stimulation of the perforant pathway (at arrows) and plotted group data (A2 and B2). Arrowheads in A1 and B1 point to the traces obtained 60 min after the last train of stimulation, the other traces (unmarked) were obtained 5 min before the first train. (C) PPF was not obvious in the dentate granule neurons from the antisense-treated (C1) and the sense-treated (C2) rats, when stimulated at interstimulus intervals of 30 or 50 ms. No significant difference was observed (C3) between the two groups (P > 0.05, unpaired t test). Plotted data are shown as means ± SEM.

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