HDAC inhibition modulates hippocampus-dependent long-term memory for object location in a CBP-dependent manner

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 hippocampusdependent 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.

Hippocampal Focal Knockout of CBP Affects Specific Histone Modifications, Long-Term Potentiation, and Long-Term Memory

“…Previously our laboratory has shown that HDAC inhibition is able to enhance long-term memory and synaptic plasticity (Vecsey et al, 2007) and rescue long-term memory deficits in CBP mutant mice when the mice are tested on object recognition (Stefanko et al, 2009), but not when they are tested on object-location recognition (Haettig et al, 2011). We therefore examined the ability of the HDAC inhibitor sodium butyrate (NaBut) to ameliorate memory impairments in Cbp flox/flox mice.…”

“…They were trained 2 weeks later, and tested at 24 h following training. During training, mice were placed in an arena with two identical objects for a 10-min training session, which we have previously shown to result in long-term memory (Stefanko et al, 2009;Roozendaal et al, 2010;Haettig et al, 2011), and then tested at 24 h later in the same arena with one familiar object moved to a novel location (OLM; Figure 6a). AAV2/ 1-Cre infused Cbp flox/flox mice exhibited no significant long-term memory for the object location as compared with Cbp + / + mice (po0.05; Figure 6b).…”

Post-training intrahippocampal inhibition of class I histone deacetylases enhances long-term object-location memory

“…Most previous studies examined the hippocampus-dependent contextual fear-conditioning task (Alarcon et al 2004;Levenson et al 2004;Vecsey et al 2007;Guan et al 2009;Peleg et al 2010) or extinction of fear memory Bredy and Barad 2008). Recently, memory enhancement by HDAC inhibitor treatment was observed for object-recognition memory (Stefanko et al 2009) and object-location memory (Haettig et al 2011). In contrast to object-location memory (Haettig et al 2011) and contextual fear conditioning (Vecsey et al 2007), the effect of HDAC inhibition on object-recognition memory does not require the CREB-CBP interaction (Stefanko et al 2009).…”

“…Recently, memory enhancement by HDAC inhibitor treatment was observed for object-recognition memory (Stefanko et al 2009) and object-location memory (Haettig et al 2011). In contrast to object-location memory (Haettig et al 2011) and contextual fear conditioning (Vecsey et al 2007), the effect of HDAC inhibition on object-recognition memory does not require the CREB-CBP interaction (Stefanko et al 2009). This mechanistic distinction is supported by an anatomical dissociation in the effect of HDAC inhibitors on different forms of object-based memory (Roozendaal et al 2010).…”

The Object Space Task shows cumulative memory expression in both mice and rats

“…We can hypothesize that successful performance on the overlapping condition involves the integration of multiple or all events in the prefrontal cortex, thereby creating a stable representation of the overlapping object location in space. While the classic version of our stable condition, namely 24h-objectdisplacement memory, is usually described as a hippocampal-dependent task (Mumby, Gaskin et al 2002;Assini, Duzzioni et al 2009;Haettig, Stefanko et al 2011;Haettig, Sun et al 2013), we cannot assume that our stable condition is also dependent on the hippocampus. Object-displacement memory requires the animal to experience only one event, in the object space task the animal experiences multiple events of the same spatial configuration.…”