Mice with mutations in four nonreceptor tyrosine kinase genes, fyn, src, yes, and abl, were used to study the role of these kinases in long-term potentiation (LTP) and in the relation of LTP to spatial learning and memory. All four kinases were expressed in the hippocampus. Mutations in src, yes, and abl did not interfere with either the induction or the maintenance of LTP. However, in fyn mutants, LTP was blunted even though synaptic transmission and two short-term forms of synaptic plasticity, paired-pulse facilitation and post-tetanic potentiation, were normal. In parallel with the blunting of LTP, fyn mutants showed impaired spatial learning, consistent with a functional link between LTP and learning. Although fyn is expressed at mature synapses, its lack of expression during development resulted in an increased number of granule cells in the dentate gyrus and of pyramidal cells in the CA3 region. Thus, a common tyrosine kinase pathway may regulate the growth of neurons in the developing hippocampus and the strength of synaptic plasticity in the mature hippocampus.

The switch from short- to long-term facilitation induced by behavioral sensitization in Aplysia involves CREB-like proteins, as well as the immediate-early gene ApC/EBP. Using the bZIP domain of ApC/EBP in a two-hybrid system, we have cloned ApCREB2, a transcription factor constitutively expressed in sensory neurons that resembles human CREB2 and mouse ATF4. ApCREB2 represses ApCREB1-mediated transcription in F9 cells. Injection of anti-ApCREB2 antibodies into Aplysia sensory neurons causes a single pulse of serotonin (5-HT), which induces only short-term facilitation lasting minutes, to evoke facilitation lasting more than 1 day. This facilitation has the properties of long-term facilitation: it requires transcription and translation, induces the growth of new synaptic connections, and occludes further facilitation by five pulses of 5-HT.

Although CREB seems to be important for memory formation, it is not known which of the isoforms of CREB, CREM, or ATF1 are expressed in the neurons that undergo long-term synaptic changes and what roles they have in memory formation. We have found a single Aplysia CREB1 gene homologous to both mammalian CREB and CREM and have characterized in the sensory neurons that mediate gill-withdrawal reflex the expression and function of the three proteins that it encodes: CREB1a, CREB1b, and CREB1c. CREB1a is a transcriptional activator that is both necessary and, upon phosphorylation, sufficient for long-term facilitation. CREB1b is a repressor of long-term facilitation. Cytoplasmic CREB1c modulates both the short- and long-term facilitation. Thus, in the sensory neurons, CREB1 encodes a critical regulatory unit converting short- to long-term synaptic changes.