Drosophila Memory Mutants

Learning in Drosophila

Classical Conditioning: Flies can learn to discriminate visual, olfactory, or tactile cues when they are paired with reward (sucrose) or punishment (shock). Fruit flies can be trained to avoid specific odors which have been paired with electrical shock: lasting a day with a single training sessions, four days in 10 training sessions in immediate succession, and greater than seven days with 10 spaced sessions at 15 minute inter-session intervals. Mushroom bodies are anatomical structures of the brain that are implicated in insect learning and memory.

Mutations that affect Associative Learning

Intact flies manage to avoid the previously shock-paired odor was the indicator of learning. Those that do not learn (or quickly forget) this task are captured and analyzed with respect to the precise mutations they carry. There are at least 2 genetically distinct forms of memory which act in parallel. The previous hypothesis where short-term memory becomes consolidated into long-term memory frinds little support in pharmacological and genetic data. With pharmacological dissection it becomes clear that consolidated memory requires multiple stages of: Acquisition (requiring intact neurotransmitter and second messenger systems), Short/Intermediate term memory (dependent on intact second messenger activation with protein phosphorylation/synthesis) and Long term memory (dependent on gene transcription due to second messenger activation). Moreover, there are at least two routes of consolidated memory, an anesthesia-resistant one involving a cAMP-dependent protein kinase, and a longer-term one involving gene expression.

Most mutations that effect memory exhibit abnormalities in the G-coupled activation of a cAMP system, which leads to diminished cAMP-dependent transription.

• rutabaga: A mutation in Calmodulin-dependent adenylate cyclase lowers cAMP levels and prevents the acquisition of memory.
• dunce: cAMP phosphodiesterase is blocked leading to high levels of cAMP and impairment of memory acquisition.
• amnesiac: affects a gene for a neuropeptide which enhances cAMP. Individuals exhibit normal acquisition but deficiencies in intermediate-term memory.
• radish: With its cellular mechanism unknown, individuals exhibit normal long-term memory, despite a disruption of intermediate term memory.

CREB (cyclicAMP-response element binding protein) plays an integral role. When CREB is disrupted long-term memory processes are not working properly. Short-term disruption of CREB is achieved by expressing a blocker under the control of heat shock promoters.

Synaptic signals induce G-protein coupled cAMP activation, which activates protein kinase A (PKA), which translocates to the nucleus and phosphorylates proteins there. Phosphorylation of CREB activates gene expression for proteins of immediate early genes (IEG) involved in the consolidation of memory. Molecular memory mechanisms identified in Drosophila and Aplysia appear to be a conserved across a broad phylogenetic range even extending to vertebrate systems (e.g., CREB mutant mice also exhibit long term memory deficits).