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, 18 (2), 71-9

HDAC Inhibition Modulates Hippocampus-Dependent Long-Term Memory for Object Location in a CBP-dependent Manner

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HDAC Inhibition Modulates Hippocampus-Dependent Long-Term Memory for Object Location in a CBP-dependent Manner

Jakob Haettig et al. Learn Mem.

Abstract

Transcription of genes required for long-term memory not only involves transcription factors, but also enzymatic protein complexes that modify chromatin structure. Chromatin-modifying enzymes, such as the histone acetyltransferase (HAT) CREB (cyclic-AMP response element binding) binding protein (CBP), are pivotal for the transcriptional regulation required for long-term memory. Several studies have shown that CBP and histone acetylation are necessary for hippocampus-dependent long-term memory and hippocampal long-term potentiation (LTP). Importantly, every genetically modified Cbp mutant mouse exhibits long-term memory impairments in object recognition. However, the role of the hippocampus in object recognition is controversial. To better understand how chromatin-modifying enzymes modulate long-term memory for object recognition, we first examined the role of the hippocampus in retrieval of long-term memory for object recognition or object location. Muscimol inactivation of the dorsal hippocampus prior to retrieval had no effect on long-term memory for object recognition, but completely blocked long-term memory for object location. This was consistent with experiments showing that muscimol inactivation of the hippocampus had no effect on long-term memory for the object itself, supporting the idea that the hippocampus encodes spatial information about an object (such as location or context), whereas cortical areas (such as the perirhinal or insular cortex) encode information about the object itself. Using location-dependent object recognition tasks that engage the hippocampus, we demonstrate that CBP is essential for the modulation of long-term memory via HDAC inhibition. Together, these results indicate that HDAC inhibition modulates memory in the hippocampus via CBP and that different brain regions utilize different chromatin-modifying enzymes to regulate learning and memory.

Figures

Figure 1.
Figure 1.
Intrahippocampal muscimol injection spread indirectly examined by c-fos immunoreactivity. (A) images are 4X magnification on the right and 20X magnification on the left. Histograms depict quantification of cell counts as a percent of vehicle. (A) Representative images showing c-fos immunoreactivity in sections of vehicle (top row) and muscimol-infused mice (bottom row). (B) Quantification shows that c-fos-immunoreactive cells are not changed in the cortex surrounding the cannula, but it is significantly decreased by 56% in the dorsal hippocampus. ***, P < 0.001. Numbers inside bars indicate sample size (n).
Figure 2.
Figure 2.
The hippocampus is engaged during object location memory retrieval. (A,C,E) Schematic diagrams for object recognition tasks. Letters (A, B, and C) in the boxes indicate objects. Gray arrow indicates a moved familiar object compared to the training. In each experiment, mice were fitted with bilateral hippocampal cannulae, allowed to recover from surgery, handled, and habituated to the context prior to a 10-min training. Animals received a bilateral injection (0.5 µL at 15 µL/h) of 1 µg/µL muscimol dissolved in PBS or PBS as a control (vehicle). Noncannulated animal did not undergo surgery or injection. (B) During a 24-h retention test, mice that received muscimol immediately after the training displayed no preference for the novel object in contrast to vehicle or noncannulated mice. (D) During a 24-h retention test, mice that received muscimol 1 h prior to the retention test displayed similar preference for the novel object compared with vehicle-treated mice. (F) During a 24-h retention test, mice that received muscimol 1 h prior to the retention test in the OLM task (moved familiar object—gray arrow) displayed a significant preference for the novel object compared to vehicle-treated mice. *, P < 0.05. Numbers inside bars indicate sample size (n).
Figure 3.
Figure 3.
HDAC inhibition enhances preference for the novel object in the ORM task, but does not affect performance in the object location-dependent OLM task. (A) Schematic for ORM task and OLM task. Letters (A, B, C) in the boxes indicate objects. Gray arrow indicates a moved familiar object compared to the training. (B) Mice administered NaBut immediately after training exhibit significant long-term memory for the familiar object in its familiar location. (C) In contrast, in the OLM task where the familiar object is placed in a different location, both vehicle- and NaBut-treated mice exhibit similar preference for both objects during the retention test, resulting in negligible discrimination. *, P < 0.05. Numbers inside bars indicate sample size (n).
Figure 4.
Figure 4.
HDAC inhibition enhances memory for the object itself in CBPKIX/KIX homozygous knock-in mice. (A) Schematic of OLM task. Letters (A, B, C) in the boxes indicate objects. Gray arrow indicates a moved object compared to the training. (B) CBPKIX/KIX mice and wild-type littermates received 10-min training period followed immediately by i.p. injection of either NaBut (1.2 g/kg in water) or vehicle (water). During the retention test, in which the familiar object is in a different location (gray arrow), wild-type mice exhibited no preference for the novel object regardless of treatment. In contrast, CBPKIX/KIX mice displayed a poor preference for the novel object, which was significantly enhanced by NaBut treatment. **, P < 0.01; ***, P < 0.001. Numbers inside bars indicate sample size (n).
Figure 5.
Figure 5.
HDAC inhibition fails to enhance object location memory in CBPKIX/KIX homozygous knock-in mice. (A) Schematic of a combined ORM and OLM task. Letters (A, B) in the boxes indicate objects. CBPKIX/KIX mice and wild-type littermates received a subthreshold 3 min training period followed immediately by i.p. injection of either NaBut (1.2 g/kg in water) or vehicle (water). (B) ORM task: Wild-type as well as CBPKIX/KIX mice exhibited a preference for the novel object if they were treated with NaBut. (C) OLM task: Here only the wild-type mice treated with NaBut exhibited a preference for the moved object. In CBPKIX/KIX mice a NaBut treatment does not enhance object location memory. *, P < 0.05; **, P < 0.01; ***, P < 0.001. Numbers over bars indicate sample size (n).

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