Poly-(ADP-ribose) polymerase-1 is necessary for long-term facilitation in Aplysia.

Activity-dependent long-term synaptic plasticity requires gene expression and protein synthesis. Identifying essential genes and studying their transcriptional and translational regulation are key steps to understanding how synaptic changes become long lasting. Recently, the enzyme poly-(ADP-ribose) polymerase 1 (PARP-1) was shown to be necessary for long-term memory (LTM) in Aplysia.

Alpha/beta-tubulin are A kinase anchor proteins for type I PKA in neurons.

Expression, localization and regulation of different cAMP-dependent protein kinase A (PKA) subunits account for specificity in the intracellular cAMP/PKA signaling pathway. In Aplysia neurons, two classes of PKA (I and II) differing in their regulatory (R) subunits have been characterized. Type I is mostly soluble in the cell body, and type II enriched at the synaptic endings.

Serotonin induces selective cleavage of the PKA RI subunit but not RII subunit in Aplysia neurons.

PKA type I and type II are activated in Aplysia neurons by stimulation with serotonin (5-HT), which causes long-term facilitation (LTF). The proteolysis of the regulatory subunit (R) is thought important for the persistent activation of PKA, which is necessary to produce LTF. In this study, we report that the type I regulatory subunit (RI) and type II regulatory subunit (RII) are differentially regulated by proteolytic cleavage.

Two mRNA-binding proteins regulate the distribution of syntaxin mRNA in Aplysia sensory neurons.

Targeting mRNAs to different functional domains within neurons is crucial to memory storage. In Aplysia sensory neurons, syntaxin mRNA accumulates at the axon hillock during long-term facilitation of sensory-motor neuron synapses produced by serotonin (5-HT). We find that the 3' untranslated region of Aplysia syntaxin mRNA has two targeting elements, the cytosolic polyadenylation element (CPE) and stem-loop double-stranded structures that appear to interact with mRNA-binding proteins CPEB and Staufen.

CREB-binding protein controls response to cocaine by acetylating histones at the fosB promoter in the mouse striatum.

Remodeling chromatin is essential for cAMP-regulated gene expression, necessary not only for development but also for memory storage and other enduring mental states. Histone acetylation and deacetylation mediate long-lasting forms of synaptic plasticity in Aplysia as well as cognition in mice. Here, we show that histone acetylation by the cAMP-response element binding protein (CREB)-binding protein (CBP) mediates sensitivity to cocaine by regulating expression of the fosB gene and its splice variant, DeltafosB, a transcription factor previously implicated in addiction.

Long-term memory requires polyADP-ribosylation.

PolyADP-ribose-polymerase 1 is activated in neurons that mediate several forms of long-term memory in Aplysia. Because polyADP-ribosylation of nuclear proteins is a response to DNA damage in virtually all eukaryotic cells, it is surprising that activation of the polymerase occurs during learning and is required for long-term memory. We suggest that fast and transient decondensation of chromatin structure by polyADP-ribosylation enables the transcription needed to form long-term memory without strand breaks in DNA.

The two regulatory subunits of aplysia cAMP-dependent protein kinase mediate distinct functions in producing synaptic plasticity.

Activation of the cAMP-dependent protein kinase (PKA) is critical for both short- and long-term facilitation in Aplysia sensory neurons. There are two types of the kinase, I and II, differing in their regulatory (R) subunits. We cloned Aplysia RII; RI was cloned previously.

Axonal transport of eukaryotic translation elongation factor 1alpha mRNA couples transcription in the nucleus to long-term facilitation at the synapse.

Long-term synaptic plasticity requires both gene expression in the nucleus and local protein synthesis at synapses. The effector proteins that link molecular events in the cell body with local maintenance of synaptic strength are not known. We now show that treatment with serotonin (5-HT) that produces long-term facilitation induces the Aplysia eukaryotic translation elongation factor 1alpha (Ap-eEF1A) as a late gene that might serve this coupling function in sensory neurons.

p38 MAP kinase mediates both short-term and long-term synaptic depression in aplysia.

At Aplysia sensory-to-motor neuron synapses, the inhibitory neuropeptide Phe-Met-Arg-Phe-NH2 (FMRFa) produces depression, and serotonin (5-HT) produces facilitation. Short-term depression has been found to result from the activation of a phospholipase A2. The released arachidonate is metabolized by 12-lipoxygenase to active second messengers.

Ubiquitination, protein turnover, and long-term synaptic plasticity.

For at least half a century, alteration of synaptic strength through growth at specific nerve terminals has been favored as the mechanism underlying long-term changes in behavior and synaptic plasticity. Although new proteins for synapses can either be synthesized locally or transported from the cell body, recent work on the postsynaptic element (dendritic spines) of cortical excitatory synapses indicates that transmission can also be modified by controlling the density of alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptors (AMPARs) in the postsynaptic density (PSD). This regulation is mediated by mono-ubiquitination, which governs turnover of AMPAR subunits by determining whether the endocytosed subunits are sent to lysosomes to be degraded or recycled back to the membrane by exocytosis.

The cytoplasmic polyadenylation element binding protein and polyadenylation of messenger RNA in Aplysia neurons.

Translation of some mRNAs in nerve terminals has been shown to be regulated by polyadenylation in an experience-dependent manner. The transcripts whose translation is controlled by regulated polyadenylation contain the cytoplasmic polyadenylation element (CPE), which binds to the highly conserved CPE-binding protein (CPEB). In Aplysia, neuron-specific actin mRNA, which has a CPE in its 3' UTR, is located both in cell bodies and at nerve endings (synaptosomes).

Integration of long-term-memory-related synaptic plasticity involves bidirectional regulation of gene expression and chromatin structure.

Excitatory and inhibitory inputs converge on single neurons and are integrated into a coherent output. Although much is known about short-term integration, little is known about how neurons sum opposing signals for long-term synaptic plasticity and memory storage. In Aplysia, we find that when a sensory neuron simultaneously receives inputs from the facilitatory transmitter 5-HT at one set of synapses and the inhibitory transmitter FMRFamide at another, long-term facilitation is blocked and synapse-specific long-term depression dominates.