Poly-(ADP-Ribose) Polymerase-1 Is Necessary for Long-Term Facilitation inAplysia

Abstract

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. Since PARP-1 decondenses chromatin, we hypothesize that this enzyme regulates the expression of specific genes essential for long-term synaptic plasticity that underlies LTM. We cloned Aplysia PARP-1 (ApPARP-1) and determined that its expression in sensory neurons is necessary for serotonin (5-HT)-mediated long-term facilitation (LTF) of sensorimotor neuron synapses. PARP enzymatic activity is also required, since transient application of PARP inhibitors blocked LTF. Differential display and RNA analysis of ganglia dissected from intact animals exposed to 5-HT identified the ribosomal RNA genes as PARP-dependent effector genes. The increase in the expression of rRNAs is long lasting and dynamic. Pulse-labeling RNA studies showed a PARP-dependent increase in rRNAs but not in the total RNA 24 h after 5-HT treatment. Moreover, the expression of both the AprpL27a (Aplysia ribosomal protein L27a) and the ApE2N (Aplysia ubiquitinconjugating enzyme E2N) mRNAs also increased after 5-HT. Thus, our results suggest that 5-HT, in part by regulating PARP-1 activity, alters the expression of transcripts required for the synthesis of new ribosomes necessary for LTF.

Histone H1 Poly[ADP]-Ribosylation Regulates the Chromatin Alterations Required for Learning Consolidation

“…The impairment we detected in long-lasting synaptic and memory processes, together with an absence of any effect on such short-term events, and earlier data indicate that PARP-1 activity plays a critical role in regulating stimulus-induced changes in macromolecular synthesis required for long-term synaptic plasticity (Cohen-Armon et al, 2004;Goldberg et al, 2009). In Aplysia, PARP-1 activation is required for the transcription of ribosomal RNAs and ribosomal proteins (Hernández et al, 2009). Conversely, NF-Band CREB-dependent gene expression is required for learning and memory stabilization in mammals (Barco et al, 2002;Levenson et al, 2004b;Vecsey et al, 2007;Ahn et al, 2008;Fontán-Lozano et al, 2009) (for review, see Alberini, 2009).…”

“…Moreover, PARP-1 activation has been shown to be required for long-term memory formation in Aplysia and mice (Cohen-Armon et al, 2004;Goldberg et al, 2009;Hernández et al, 2009), although the molecular mechanisms involved have not yet been described. Here we confirm that PARP-1 activity is needed in the mouse hippocampus to establish long-lasting synaptic plasticity events such as learning consolidation and long-lasting LTP.…”

“…Depolarization and exposure of cortical neurons to neuronal growth factor have been shown to activate PARP-1 in the absence of DNA damage (Homburg et al, 2000;Visochek et al, 2005). Moreover, it was shown recently that PARP-1 activation is required for long-term neuronal plasticity in Aplysia and mice (Cohen-Armon et al, 2004;Goldberg et al, 2009;Hernández et al, 2009). However, the mechanisms by which PARP-1 operates in learning and memory are not well known.…”

Cellular and subcellular localization of PKMζ

“…In particular, the localization of PKMz to chromatin raises the possibility that the kinase may be important for epigenetic regulation of gene expression, a process well known to regulate synaptic plasticity [41,42], initial memory consolidation [43,44], as well as memory maintenance [45]. Within nuclei, PKCz has been reported to phosphorylate nucleolin, an important regulator of chromatin remodelling and gene expression [46,47].…”

Epigenetic Treatments for Cognitive Impairments

“…Interestingly, although poly-ADP ribosylation and PARP1 activity are most well known for their role in DNA repair following damage, PARP1 activation has been shown to increase in cortical neurons following depolarization (Homburg et al, 2000). Likewise, PARP1 is required for long-term synaptic facilitation and long-term memory in aplysia, suggesting a functional role in the nervous system (Cohen-Armon et al, 2004;Hernandez et al, 2009). Likewise, in mouse models, poly-ADP ribosylation is increased at the histone linker protein H1 following novel object exposure, and PARP1 is required for hippocampal LTP and novel object recognition memory (Fontan-Lozano et al, 2010).…”