|Evolution has equipped multicellular organisms with ever more sophisticated means of processing information about the environment they live in. The hippocampus has been shown to be one of the most important structures of the mammalian brain for information processing with respect to learning and memory formation.
In general, memories stored for seconds to minutes are known as short-term memories (STMs), while long-term memories (LTMs) may be stored for hours, days and up to years. Research on the cellular and molecular mechanisms of memory consolidation has revealed that LTM formation as well as a cellular correlate of this process – late-phase long-term potentiation (LTP) – depend on DE NOVO protein synthesis and transcription. The synaptic tagging and capture (STC) hypothesis has been formulated as a theoretical basis of this process.
Chromatin plasticity, including dynamic histone acetylation has been demonstrated to play a positive role in long-term memory consolidation and regulation of plasticity-related transcription. Inhibition of histone deacetylases (HDACi) has beneficial effects in several disease models and enhances memory formation across multiple species. Loss of histone acetyltransferase (HAT) function on the other hand has negative effects on memory consolidation. Kat2a is a HAT associated with stimulus-dependent transcriptional activation. However, its function and targets in the adult brain have not been explored yet.
With increasing human life span, aging is becoming a major challenge in modern societies. As in many other aspects, the brain also holds an exceptional position when it comes to aging. One of the earliest symptoms of the aging brain is age-associated memory impairment (AAMI), which is a normal though commonly undesirable process, manifesting itself by difficulties in acquisition of new memories and by increased forgetfulness. Brain aging is also accompanied by massive transcriptional changes. However, a detailed, homogenous picture of the transcriptome of the aging mouse hippocampus, especially towards the end of an individual’s life span, has not been drawn yet. Accumulating evidence suggests that chromatin-related mechanisms may be involved in the regulation of transcriptional aging. However, data on the contribution of histone acetylation remains incomplete.
Here, we provide extensive evidence supporting a role for Kat2a in learning and memory. The data shows strong Kat2a expression in the hippocampal neurons, especially in the CA1. Using elaborate behavioral testing, we show impairment of hippocampus-dependent LTM formation upon Kat2a deletion from excitatory forebrain neurons. This finding is further supported by electrophysiological data revealing impaired LTP in the CA1 region. Interestingly, stimulus-dependent mRNAome profiling in the CA1 of conditional knockout and control mice following a novelty-exposure paradigm showed downregulation of several genes related to neuronal activity, which are likely target genes of Kat2a activity. Interestingly, Kat2a overexpression in the DG did not result in enhancement of LTM formation, and even led to impaired performance in the Morris water maze, used for spatial memory testing. The findings are discussed with respect to stimulus-dependent gene expression during memory consolidation and in the light of the STC hypothesis.
In a second set of experiments we assessed histone acetylation in the hippocampus of aged mice. While we found no evidence for altered levels of bulk histone acetylation or differential HAT activity, we observed reduced HDAC activity in mice towards the end of lifespan (EOL), that was not associated with reduced expression of Hdac2 or Hdac3. Assuming this to be a compensatory mechanism, we tried to facilitate this compensation at an earlier stage using HDACi. Indeed, long-term HDACi treatment rescued the AAMI phenotype that is observed in aged mice.
In addition, transcriptional changes that accompany the aging process in the hippocampus were detected using whole-transcriptome mRNA sequencing as well as microarray technology. Together, both methods revealed a transcriptional signature of aging highly associated with a pro-inflammatory milieu, which may be caused by ineffective aggregate clearance. Increased intragenic H3K9 acetylation was associated with at least one of these genes, C4b, demonstrating activatory regulation. Implications of these findings for brain aging in general as well as late-onset Alzheimer’s disease in particular are presented and discussed.