16 August 2011. Presenilin-1 is perhaps best known as the business end of the γ-secretase complex that cleaves amyloid-β from its precursor. But over the years, non-catalytic roles for the protease have been proposed, including regulation of calcium release from intracellular stores. Yet another function for presenilin-1 (PS1) debuted in the August 14 Nature Neuroscience online. Researchers led by Jane Sullivan at the University of Washington, Seattle, reported that PS1 modulates homeostatic synaptic scaling, a type of synaptic plasticity that functions at the level of neuronal networks. Interestingly, PS1 regulates this scaling independently of both γ-secretase activity and calcium mobilization, suggesting a completely new modus operandi for this transmembrane protease. “This is very solid work and clearly an interesting observation,” said Ilya Bezprozvanny, University of Texas Southwestern Medical Center, Dallas. “Though how it relates to Alzheimer’s disease will depend on the role of this [synaptic scaling] mechanism in maintaining network activity in the brain,” he told ARF. The study of homeostatic scaling is still in its infancy and has mostly been conducted in vitro, but hints of its in-vivo relevance have emerged, Sullivan told ARF. “We’re opening up a new avenue for exploration with the possibility of new treatment strategies,” she said.
Homeostatic scaling is one of several mechanisms that keep neurons firing within optimal range. Neurons have the ability to respond to their environment by boosting or suppressing synaptic responses, but that can’t become runaway, said Sullivan. Homeostatic scaling evolved to ensure neurons don’t become over- or underactive in response to inputs. Research on the phenomenon has focused mostly on neuronal cultures from young animals, but more recent work has uncovered the same property in adult mice.
First author Kara Pratt made the connection between presenilin-1 and synaptic scaling when characterizing the properties of PS1-null mutants. Pratt was a graduate student at Gina Turrigiano's lab at Brandeis University, Waltham, Massachusetts, before joining Sullivan’s group as a postdoc. Turrigiano is one of the pioneers of homeostatic scaling research, and, being familiar with its properties, Pratt recognized that the PS1-negative neurons behaved as though deficient in the process. A typical test is to completely block neuronal activity with tetrodotoxin for 24 to 48 hours, then look for an uptick above baseline once that blockade is relieved. Unlike wild-type neurons, hippocampal neurons from PS1-negative mice failed to scale up electrical activity in this paradigm. Neurons expressing PS1 with the M146V familial AD mutation, which retains γ-secretase activity, also failed to scale up activity, while cells treated with a γ-secretase inhibitor behaved as did wild type. The evidence pointed to a γ-secretase-independent control by PS1 over synaptic scaling.
How does PS1 regulate this plasticity? Turrigiano’s group found that homeostatic scaling relies on a drop in calcium concentration in the soma and a quenching of calmodulin kinase IV (CaMKIV) activity (Ibata et al., 2008). Since Bezprozvanny and others linked PS1 to calcium mobilization (see ARF related news story and ARF news story), Sullivan said they expected that PS1-negative neurons jeopardized scaling because they maintained their calcium and CaMKIV activity. “But actually, that was not it. It was not operating in the way we expected,” said Sullivan. Scaling failed in PS1-null neurons even when the researchers blocked activation of the calmodulin kinase.
Instead, Sullivan pieced together a totally different scenario. The researchers had used a virus vector to express wild-type presenilin to rescue the synaptic defect. The vector was a gift from Rachael Neve. When working at McLean Hospital, Belmont, Massachusetts, Neve discovered, together with researchers at Nikolaos Robakis’s lab at the Mount Sinai School of Medicine, New York, that PS1 knockouts fail to activate Akt kinase (see ARF related news story on Baki et al., 2008). Sullivan realized that a class of compound Neve used to block Akt, phosphatidylinositol-3-kinase inhibitors, was recently reported to prevent homeostatic synaptic scaling. “We thought, 'Aha! Perhaps Akt deficiency is to blame,’” said Sullivan. Sure enough, when Pratt introduced a constituently active Akt into neurons expressing the M146V PS1, she rescued the scaling defect. The results suggest that Akt signaling may be deficient in familial, and even perhaps sporadic AD, according to the researchers.
“These finding are inherently interesting in that they link mutations known to cause AD with a mechanism of impaired synaptic scaling, thereby supporting an increasingly investigated hypothesis that there are subtle, underlying deficits in synaptic function occurring long before overt symptoms of AD pathology,” wrote Beth Stutzmann, Rosalind Franklin University, Chicago, Illinois, in an e-mail to ARF (see full text below).
Sullivan is interested in testing whether homeostatic synaptic scaling is also deficient in other models of AD. She noted recent work linking Aβ to caspase-3 activation, which has been implicated in regulation of Akt activation (see Jo et al., 2011). “There may be ways to generate the same [homeostatic synaptic scaling] deficit with Aβ, so we could possibly extend these observations to include non-presenilin-based causes,” she said.—Tom Fagan.
Pratt KG, Zimmerman EC, Cook DG, Sullivan JM. Presenilin-1 regulates homeostatic synaptic scaling through Akt signaling. Nat Neurosci. 2011 Aug 14. Abstract