CREB Binding Protein Is Required for Both Short-Term and Long-Term Memory Formation

Abstract

CREB binding protein (CBP) is a transcriptional coactivator with histone acetyltransferase activity. Our prior study suggested that CBP might be a key target of presenilins in the regulation of memory formation and neuronal survival. To elucidate the role of CBP in the adult brain, we generated conditional knock-out (cKO) mice in which CBP is completely inactivated in excitatory neurons of the postnatal forebrain. Histological analysis revealed normal neuronal morphology and absence of age-dependent neuronal degeneration in the CBP cKO cerebral cortex. CBP cKO mice exhibited robust impairment in the formation of spatial, associative, and object-recognition memory. In addition to impaired long-term memory, CBP cKO mice also displayed deficits in short-term associative and object-recognition memory. Administration of a histone deacetylase inhibitor, trichostatin A, rescued the reduction of acetylated histones in the CBP cKO cortex but failed to rescue either short-or long-term memory deficits, suggesting that the memory impairment may not be caused by general reduction of histone acetyltransferase activity in CBP cKO mice. Further microarray and Western analysis showed decreased expression of calcium-calmodulin-dependent kinase isoforms and NMDA and AMPA receptor subunits in the cerebral cortex of CBP cKO mice. Collectively, these findings suggest a crucial role for CBP in the formation of both short-and long-term memory.

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

“…p300 therefore may be expected to compensate for a lack of CBP. However, we observed no change in p300 in the region of CBP deletion ( Figure 1) and therefore, similarly to findings in other CBP mutant mice (Kasper et al, 2006;Chen et al, 2010), it does not appear that p300 is being upregulated to compensate for a loss of CBP.…”

“…To date, six different types of Cbp mutant mice have been generated to examine the role of CBP in memory (Oike et al, 1999;Bourtchouladze et al, 2003;Alarcon et al, 2004;Korzus et al, 2004;Wood et al, 2005Wood et al, , 2006Chen et al, 2010). However, none of these Cbp genetically modified mice were designed to target a single brain region and only one generated a complete knockout of CBP, as a homozygous knockout of Cbp results in embryonic lethality (Tanaka et al, 1997).…”

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…Studies examining the effect of a partial or total loss of CBP function show the involvement of its HAT activity in LTP and LTM, and suggest that CBP is not required for the formation of short-term memory (STM) [47,[199][200][201][202]. Nevertheless, another study using a conditional model with complete CBP inactivation in excitatory neurons of the forebrain showed an impairment of both memory types [203]. However, more recent studies confirm CBP involvement in LTM.…”

“…Interestingly, at least one wild-type allele of cbp was required to mediate the effects of HDAC inhibition on memory functions [215]. A supportive study demonstrated that HDACi were inefficient in a complete knock down of cbp [203]. Thus, simply inducing a histone hyperacetylated state with HDACi does not adequately replace HAT activation, at least in certain functions (i.e., memory formation), likely reflecting the other potential roles of HAT (e.g., CBP).…”

The endocannabinoid system in normal and pathological brain ageing

“…A crucial role of CREB signalling in memory formation was found in both invertebrates and vertebrates [30]. Generally, decreased CREB activity was associated with learning impairments in healthy aged animals [31,32] and with cognitive deficits in animal models of neurodegenerative disorders [33][34][35]. Importantly, the level of phosphorylated CREB and the activity-induced increase in CREB phosphorylation is diminished in ageing [36,37], and this itself may influence the ageing process [38,39].…”