Dissociable roles for histone acetyltransferases p300 and PCAF in hippocampus and perirhinal cortex‐mediated object memory

Abstract

The importance of histone acetylation for certain types of memory is now well established. However, the specific contributions of the various histone acetyltransferases to distinct memory functions remain to be determined; therefore, we employed selective histone acetyltransferase protein inhibitors and short-interference RNAs to evaluate the roles of CREB-binding protein (CBP), E1A-binding protein (p300) and p300/CBP-associated factor (PCAF) in hippocampus and perirhinal cortex (PRh)-mediated object memory. Rats were tested for short- (STM) and long-term memory (LTM) in the object-in-place task, which relies on the hippocampus and PRh for spatial memory and object identity processing, respectively. Selective inhibition of these histone acetyltransferases by small-interfering RNA and pharmacological inhibitors targeting the HAT domain produced dissociable effects. In the hippocampus, CBP or p300 inhibition impaired long-term but not short-term object memory, while inhibition of PCAF impaired memory at both delays. In PRh, HAT inhibition did not impair STM, and only CBP and PCAF inhibition disrupted LTM; p300 inhibition had no effects. Messenger RNA analyses revealed findings consistent with the pattern of behavioral effects, as all three enzymes were upregulated in the hippocampus (dentate gyrus) following learning, whereas only CBP and PCAF were upregulated in PRh. These results demonstrate, for the first time, the necessity of histone acetyltransferase activity for PRh-mediated object memory and indicate that the specific mnemonic roles of distinctive histone acetyltransferases can be dissociated according to specific brain regions and memory timeframe.

Contrasting roles for DNA methyltransferases and histone deacetylases in single-item and associative recognition memory

“…However, other studies have shown that increases in histone acetylation in the mPFC enhanced fear extinction (Bredy et al, 2007) and trace fear memory (Sui et al, 2012). It is possible therefore that the effects of histone acetylation in memory may be task-specific, however a recent study using the OIP task found that HAT inhibition in the HPC and PRh impaired associative recognition memory (Mitchnick et al, 2016), indicating that histone acetylation in other brain areas is required for OIP task performance.…”

“…Histone acetylation has been shown to be critical for the formation of fear and spatial memory (Guan et al, 2009, Sui et al, 2012) and transgenic mice in which HAT activity is inhibited showed significant impairments in spatial memory and novel object recognition. HAT inhibition in the PRh or the HPC was also found to impair object-place associative recognition memory (Mitchnick et al, 2016). Conversely, HDAC inhibition has been shown to rescue the deficit in object recognition memory observed after HAT mutation (Korzus et al, 2004) and to enhance object recognition memory following a shortened same phase which did not result in robust memory in control animals (Fontán-Lozano et al, 2008, Stefanko et al, 2009, Haettig et al, 2011).…”

Epigenetic Mechanisms of Learning and Memory: Implications for Aging

“…This was quickly translated to rodents, where numerous studies show that learning induces histone acetylation [ 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 ] and the manipulation of histone acetylation can alter memory. Specifically, genetic or pharmacological manipulation of HDACs/HATs have generally established that increasing histone acetylation enhances memory, whereas decreasing histone acetylation impairs memory [ 107 , 109 , 111 , 112 , 113 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 ].…”

Plasticity Mechanisms of Memory Consolidation and Reconsolidation in the Perirhinal Cortex

“…Using an hippocampal dependent version of the OR task, the object in place task, Mitchnick, Creighton, O'Hara, Kalisch and Winters [98] found that inhibition of DNA methyl transferases (DNMTs) impairs long-but not short-term in both PRh and HP, but there is a dissociation in the epigenetic mechanisms involved in both regions, with de novo DNMT3a upregulated and involved in hippocampal effects and DNMT1 for perirhinal effects. Comparably, in the hippocampus inhibition of CREB-binding protein (CBP) and p300 acetyltransferases impaired long-but not short-term memory, while in the PRh CBP and PCAF inhibition disrupted long term memory [99]. Remarkably, there seems to be different epigenetic mechanisms operating in brain regions that process different kinds of information.…”