Genes to Remember

Christina Alberni

Journal of Experimental Biology. 1999.

• How does the brain form and recall memories?

• What are the biological changes that serve as the bases of memory?

• Antibiotics that inhibit protein synthesis also inhibit long-term memory formation when given during learning.

• Many studies in species ranging from invertebrates to mammals show that a fundamental and conserved pre-requisite for long-term memory formation is the expression of genes and protein synthesis during and immediately after learning.

• This critical period coincides with the consolidation phase of memory, the initial period necessary to transform incoming information into stable and storable modifications.

• If gene expression is blocked after this critical period is over, memory forms normally.

Memory in invertebrates: marine snail

• Aplysia calofornica is a marine snail with a relatively small number of large and readily identifiable neurons.

• It has been used in studies of memory for over 30 years.

• The form of learning best characterized in the snail is sensitization of the gill and siphon withdrawal reflex.

• When a touch stimulus to the animal is combined with a noxious treatment (chemical, electrical), the animal subsequently reacts more strongly (is sensitized to) the touch stimulus.

• When a sensitizing (noxious) stimulus is applied, it produces an increase in neurotransmitter release, called facilitation, at the synapses that connect the sensory neuron (which senses the stimulus) to the motor neuron (which causes the gill and siphon withdrawal reflex).

• Facilitation is mediated by the action of the neurotransmitter 5-HT, which is released by regulatory neurons and acts on the serotonin receptors of the sensory neurons.

• Sensory neurons respond to 5-HT with an increase in cAMP level and the activation of camp-dependent protein kinase A (PKA).

• Long-term facilitation requires the activity of transcription factors belonging to the cAMP response-element binding protein (CREB) family.

• CREB’s appear to be the genetic switch that turns on the expression of genes necessary for long-term memory.

Memory in invertebrates: fruit fly

• Drosophila melanogaster is the common fruit fly

• a favorite model organism for genetic studies for many years.

• Benzer and colleagues used Pavlovian olfactory learning to train flies to avoid an odor paired with an electrical shock and identified dunce and rutabaga, two different single-gene mutations that impair associative learning.

• Biochemical and molecular analysis showed that the two genes encode cAMP-related proteins.

• Tully and colleagues clone the Drosophila CREB gene, dCREB2.

• They showed that a dCREB2 knock-out completely blocked long-term memory, while increased expression of dCREB2 improved long-term memory formation.

Memory in mammals: mice and humans

• In mammals, CREB is a large family of transcription factors generated by alternative splicing.

• CREB is required for long-term memory formation in mammals, and mutations in CREB proteins impair memory formation.

• Current research focuses on where and when in the brain CREB is activated during learning, what signals induce CREB response, and which CREB-regulated genes are required for memory formation.

• The hippocampus is part of the brain that has long been known from clinical studies to be involved in memory formation.

• Lesions of the hippocampus in humans cause an inability to store new information into long-term memory.

• Recall of previously-stored information, however, is relatively unaffected.

• Following training, in the hippocampus, cAMP concentration and PKA expression and activity are increased, CRE-dependent expression is activated and CREB phosphorylation is increased, suggesting that CREB response is modulated by the cAMP/PKA signaling pathway in mammals as in invertebrates.