Authors: Audrey Coulon, Florian Rabiller, Mari Takalo, Avishek Roy, Alexandre Pelletier, Henna Martiskainen, Dolores Siedlecki-Wullich, Nina Lannette-Weimann, Naďa Majerníková, Arthur Grenon, Vance Gao, Anaël Erhardt, Anne Pernodet, Morgane Lemaire, Floriane Limoge, Pauline Walle, Tiago Mendes, Karine Guyot, Célia Lemeu, Lukas-Iohan Carvalho, Ana Raquel Melo de Farias, Marc Hulsman, Chloé Najdek, Alejandra Freire-Regatillo, Orthis Saha, Philippe Amouyel, Camille Charbonnier, Jean-François Deleuze, Orio Dols-Icardo, Heli Jeskanen, Roosa-Maria Willman, Teemu Kuulasmaa, Mitja Kurki, John Hardy, Sami Heikkinen, Henne Holstege, Petra Mäkinen, Gaël Nicolas, Simon Mead, Michael Wagner, Alfredo Ramirez, Tuomas Rauramaa, Aarno Palotie, Rebecca Sims, Hilkka Soininen, John van Swieten, Julie Williams, Céline Bellenguez, Carla Gelle, Erwan Lambert, Marcos R. Costa, Julia TCW, Enrico Glaab, Anne-Marie Ayral, Florie Demiautte, Benjamin Grenier-Boley, Manon Muntaner, Delphine Eberlé, Séverine Deforges, Joel T. Haas, Devrim Kilinc, Christophe Mulle, Julien Chapuis, Mikko Hiltunen, Julie Dumont, and Jean-Charles Lambert
Nature Genetics, 14 August 2026
Maestro Pro MEA recordings reveal reduced neuronal firing and bursting following PLCG2 downregulation, linking an Alzheimer’s disease risk gene to impaired synaptic function.
Genetic studies have identified numerous loci associated with Alzheimer’s disease risk, but how many of these genes contribute to neuronal dysfunction remains unclear. In this study, researchers screened 198 genes located within 76 Alzheimer’s disease-associated loci to identify genes that influence synaptic density and function. Among the strongest hits was PLCG2, a gene that has been studied primarily in microglia but is also expressed in neurons.
Using Axion BioSystems’ Maestro Pro MEA system, the researchers measured electrophysiological activity in both rat primary neuronal cultures and human neuronal cultures. PLCG2 downregulation significantly reduced burst frequency in rat neurons and produced similar functional deficits in human cultures, including decreased burst frequency and mean spike frequency. Additional experiments showed reduced dendritic complexity and spine density, impaired neuronal excitability, and weakened excitatory synaptic transmission.
Importantly, PLCG2 downregulation in human neuronal cultures also increased amyloid-β levels and Tau phosphorylation, while restoring PLCG2 expression reversed these changes. Very rare PLCG2 loss-of-function variants were associated with substantially increased Alzheimer’s disease risk, further supporting a role for PLCγ2 in neuronal and synaptic function. Together, the findings suggest that reduced PLCG2 activity may contribute to Alzheimer’s disease through both synaptic dysfunction and increased disease-associated pathology.
