Neurofibromatosis type 1 (NF1) is a dominant genetic disorder that causes tumors 
of the peripheral nervous system. In addition, >40% of afflicted children have 
learning difficulties. The NF1 protein contains a highly conserved 
GTPase-activating protein domain that inhibits Ras activity, and the C-terminal 
region regulates cAMP levels via G-protein-dependent activation of adenylyl 
cyclase. Behavioral analysis indicates that learning is disrupted in both 
Drosophila and mouse NF1 models. Our previous work has shown that defective cAMP 
signaling leads to the learning phenotype in Drosophila Nf1 mutants. In the 
present report, our experiments showed that in addition to learning, long-term 
memory was also abolished in Nf1 mutants. However, altered NF1-regulated Ras 
activity is responsible for this defect rather than altered cAMP levels. 
Furthermore, by expressing clinically relevant human NF1 mutations and deletions 
in Drosophila Nf1-null mutants, we demonstrated that the GAP-related domain of 
NF1 was necessary and sufficient for long-term memory, whereas the C-terminal 
domain of NF1 was essential for immediate memory. Thus, we show that two 
separate functional domains of the same protein can participate independently in 
the formation of two distinct memory components.