Impaired long-term stability of CA1 place cell representation in mice lacking the transcription factor zif268/egr1

Abstract

Zif268 is a transcriptional regulator that plays a crucial role in maintenance of the late phases of hippocampal long-term potentiation (LTP) and consolidation of spatial memories. Because the hippocampal place cell system is essential for long-term spatial memory, we tested the hypothesis that zif268 is required for long-term stability of hippocampal place cell representations by recording CA1 place cells in mice lacking zif268. We found that zif268 gene deletion destabilized the representation of a familiar environment after exposure to a novel environment and impaired the long-term (24 h), but not short-term (1 h), stability of newly formed representations. These impairments could be rescued by repeated exposure to the novel environment, however. These results indicate that zif268 contributes to the long-term stability of spatial representations in CA1 and support the notion that the long-term stability of place cell representations requires transcription-dependent mechanisms similar to those observed in LTP.

Fig. 1.

Rotational remapping of place fields in the familiar environment after exposure to the novel environment in zif268 KO mice. (A) S2/S4 similarity scores in the first 4 recording sequences. *P < .05, NS (not significant), P > .05. (B) Distribution in number of cells of the rotation angles (20° bins) corresponding to S2/S4 Z_Max pooled for the first 2 sequences in WT and zif268 KO mice (WT: n = 50, mean angle = 0.925°, SD = 4.11°, r = 0.879; zif268: n = 63, mean angle = 5.9°, SD = 16.34°, r = 0.305). In zif268 KO mice, 42.9% (26/63) of cells had fields that shifted (rotation angle exceeding 0° ± 30°). A V test performed on these cells (with cells with stable fields excluded from the analysis) indicated that the rotation angles were not homogeneously distributed but were clustered around 180°, indicating a rotational bias (V test, u = 4.791; P < .001). (C) Rate maps illustrating remapping in S3 (new environment) and rotational remapping in S4 (familiar environment) in zif268 KO mice. The dashed line indicates the 1-h delay.

Fig. 2.

Long-term stability of place fields in the novel environment is impaired in zif268 KO mice. (A) Similarity scores for S1/S6 correlations for recording sequences 1 and 2 and S5/S7 correlations for recording sequences 1 and 2 and recording sequences 3 and 4 in WT and zif268 KO mice. **P < .01; NS (non significant), P > .05. (B) Distribution in number of cells of the rotation angles (20° bins) corresponding to S5/S7 Z_Max pooled for the first 2 recording sequences (WT: n = 39, mean angle = 359.7°, SD = 31.2°, r = 0.862; zif268: n = 36, mean angle = 354.9°, SD = 82.72°, r = 0.353). In S7, 92% of the fields (36/39) in WT mice and in 42% of the fields (15/36) in zif268 KO mice were found to be stable (χ² = 22.16, P < .001). (C) Rate maps illustrating remapping in S7 in zif268 KO mice. The dashed line indicates the 1-h delay; the continuous line, the 24-h delay.