Bryostatin Enhancement of Memory inHermissenda

Abstract

Abstract. Bryostatin, a potent agonist of protein kinase C (PKC), when administered to Hermissenda was found to affect acquisition of an associative learning paradigm. Low bryostatin concentrations (0.1 to 0.5 ng/ml) enhanced memory acquisition, while concentrations higher than 1.0 ng/ml down-regulated the pathway and no recall of the associative training was exhibited. The extent of enhancement depended upon the conditioning regime used and the memory stage normally fostered by that regime. The effects of two training events (TEs) with paired conditioned and unconditioned stimuli, which standardly evoked only short-term memory (STM) lasting 7 min, were-when bryostatin was added concurrently-enhanced to a long-term memory (LTM) that lasted about 20 h. The effects of both 4-and 6-paired TEs (which by themselves did not generate LTM), were also enhanced by bryostatin to induce a consolidated memory (CM) that lasted at least 5 days. The standard positive 9-TE regime typically produced a CM lasting at least 6 days. Low concentrations of bryostatin (Ͻ0.5 ng/ml) elicited no demonstrable enhancement of CM from 9-TEs. However, animals exposed to bryostatin concentrations higher than 1.0 ng/ml exhibited no behavioral learning.Sharp-electrode intracellular recordings of type-B photoreceptors in the eyes from animals conditioned in vivo with bryostatin revealed changes in input resistance and an enhanced long-lasting depolarization (LLD) in response to light. Likewise, quantitative immunocytochemical measurements using an antibody specific for the PKC-activated Ca 2ϩ /GTP-binding protein calexcitin showed enhanced antibody labeling with bryostatin.Animals exposed to the PKC inhibitor bisindolylmaleimide-XI (Ro-32-0432) administered by immersion prior to 9-TE conditioning showed no training-induced changes with or without bryostatin exposure. However, if animals received bryostatin before Ro-32, the enhanced acquisition and demonstrated recall still occurred. Therefore, pathways responsible for the enhancement effects induced by bryostatin were putatively mediated by PKC.Overall, the data indicated that PKC activation occurred and calexcitin levels were raised during the acquisition phases of associative conditioning and memory initiation, and subsequently returned to baseline levels within 24 and 48 h, respectively. Therefore, the protracted recall measured by the testing regime used was probably due to bryostatininduced changes during the acquisition and facilitated storage of memory, and not necessarily to enhanced recall of the stored memory when tested many days after training.

Chemical Defenses: From Compounds to Communities

“…3) has the potential to counter the effects of depression and dementia, making it a promising therapeutic agent for Alzheimer's disease and other central nervous system disorders in humans Alkon, 2005, 2006;Alkon et al, 2007). PKC activation by low concentrations of bryostatins has been shown to enhance long-term memory in the nudibranch Hermissenda Kuzirian et al, 2006). Although clinical testing has revealed that the interactions of bryostatins with PKC can mediate processes in animals ranging from inhibition of cell growth to activation of neurological processes, further work is necessary to determine the biochemical mechanisms by which bryostatins deter predators.…”

Localization of ‘Candidatus Endobugula sertula’ and the bryostatins throughout the life cycle of the bryozoan Bugula neritina

“…sertula' produces the bryostatins (Davidson et al, 2001), a group of complex polyketides that protect B. neritina larvae from predation (Lindquist and Hay, 1996;Lopanik et al, 2004). The bryostatins, first isolated from B. neritina (Pettit et al, 1982), also show potential for treatment of Alzheimer's disease and a variety of cancers (Kraft et al, 1986;Parkinson et al, 1994;Alkon, 2005, 2006;Kuzirian et al, 2006). Research over the past decade has confirmed the symbiotic source of the bryostatins, identified the bryostatin biosynthetic genes from 'E.…”

Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity

“…Of additional clinical significance, bryostatin enhances learning and extends memory in animal models (32,33), which is attributable in part to its ability to induce synaptogenesis (34). These activities suggest that bryostatin or a more readily This article is a PNAS Direct Submission.…”