Postnatal Role for Histone Deacetylase 1 and 2 in Behavioral and Neuronal Homeostasis




Mahgoub, Melissa

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Epigenetics is a dynamic process that can change gene expression without alterations in the DNA sequence. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) can influence gene activity by inducing either an active or inactive chromatin state, respectively. Accumulating in vitro data has demonstrated a crucial function for histone acetylation and deacetylation in regulating the cellular and behavioral mechanisms underlying synaptic plasticity and learning and memory. In trying to delineate the roles of individual HDACs, genetic tools have been used to manipulate HDAC expression in rodents, uncovering distinct contributions of separate HDACs in regulating the processes of memory formation. Moreover, recent findings have suggested an important role for inhibitors of HDACs in enhancing learning and memory as well as ameliorating symptoms related to neurodegenerative diseases with recent attention focused on HDAC1 and HDAC2. The overlying goal of my Ph.D. thesis has been to further delineate how the loss of the HDAC1 and HDAC2 genes affects learning and memory and other complex behaviors. We accomplished this in three separate studies. First, we examined whether the individual loss of HDAC1 or HDAC2 postnatally could recapitulate the memory enhancements observed in previous pharmacological studies. We found that a conditional postnatal deletion of HDAC2 improves learning and memory behavior, while no effects were observed in HDAC1 knockout mice. Next, since HDAC1 and HDAC2 share a high degree of sequence homology we examined whether the simultaneous deletion of both genes from the postnatal brain would result in beneficial effects on learning and memory compared to the loss of the individual genes. We found that the loss of both HDAC1 and HDAC2 leads to early lethality in conditional double knockout mice, suggesting redundant functions of these HDACs in postmitotic neurons. Finally, after observing and characterizing an excessive grooming phenotype in conditional HDAC1/2 double knockout mice we mechanistically attributed this phenotype to dysregulation of SAP90/PSD-95-associated protein 3 (SAPAP3), a key protein linked to the development of obsessive-compulsive disorder (OCD). In summary, we have characterized important roles for HDAC1 and HDAC2 in mechanisms underlying learning and memory, and have uncovered a novel role for HDAC1/2 in mediating obsessive-compulsive-like behaviors.

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