To explore the role of protein kinase A (PKA) in the late phase of long-term potentiation (L-LTP) and memory, we generated transgenic mice that express R(AB), an inhibitory form of the regulatory subunit of PKA, only in the hippocampus and other forebrain regions by using the promoter from the gene encoding Ca2+/ calmodulin protein kinase IIalpha. In these R(AB) transgenic mice, hippocampal PKA activity was reduced, and L-LTP was significantly decreased in area CA1, without affecting basal synaptic transmission or the early phase of LTP. Moreover, the L-LTP deficit was paralleled by behavioral deficits in spatial memory and in long-term but not short-term memory for contextual fear conditioning. These deficits in long-term memory were similar to those produced by protein synthesis inhibition. Thus, PKA plays a critical role in the consolidation of long-term memory.

Histone deacetylase (HDAC) inhibitors increase histone acetylation and enhance both memory and synaptic plasticity. The current model for the action of HDAC inhibitors assumes that they alter gene expression globally and thus affect memory processes in a nonspecific manner. Here, we show that the enhancement of hippocampus-dependent memory and hippocampal synaptic plasticity by HDAC inhibitors is mediated by the transcription factor cAMP response element-binding protein (CREB) and the recruitment of the transcriptional coactivator and histone acetyltransferase CREB-binding protein (CBP) via the CREB-binding domain of CBP. Furthermore, we show that the HDAC inhibitor trichostatin A does not globally alter gene expression but instead increases the expression of specific genes during memory consolidation. Our results suggest that HDAC inhibitors enhance memory processes by the activation of key genes regulated by the CREB:CBP transcriptional complex.

Brain-derived neurotrophic factor (BDNF) is expressed at high levels in hippocampal neurons, and its expression is modulated by neural activity. Knockout mice can be used to study the roles of molecules like BDNF in synaptic plasticity with more molecular specificity than is possible using pharmacological approaches. Because in conventional knockouts the disrupted gene product is absent in all tissues throughout the life of the animal, developmental effects may complicate the interpretation of deficits in the adult. Rescue experiments can help to distinguish between developmental and acute requirements for the missing gene product. We here demonstrate that treatment of hippocampal slices from BDNF knockout mice with recombinant BDNF completely reverses deficits in long-term potentiation and significantly improves deficits in basal synaptic transmission at the Schaffer collateral-CA1 synapse. Thus, BDNF has an acute role in hippocampal synaptic function.