The role of mammalian CAMTA proteins in transcriptional control of neuronal morphology and long-term memory

• Applicant: Professor Dr. Hilmar Bading
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2013 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 244445106

The formation of long-term memories requires long-lasting structural and functional adaptations of neurons. To instruct these adaptations, synaptic activity initiates calcium-dependent signaling cascades that lead to changes in neuronal gene expression. This synapse-to-nucleus communication involves the activation of calcium/calmodulin-dependent transcriptional regulators that include CREB, CBP, MeCP2, and MEF2. Recently a novel family of transcriptional regulators, the so-called calmodulin-binding transcription activator (CAMTA) proteins, were identified. The two mammalian CAMTA family members, CAMTA1 and CAMTA2, are highly expressed in the mouse and human brain. As calmodulin-dependent transcriptional regulators, they might be involved in synaptic activity-dependent gene expression that underlies memory formation. In line with this notion, genetic studies reported an association between CAMTA1 gene polymorphisms and cognitive performance in humans. Our recent unpublished experiments revealed that shRNA mediated knock-down of CAMTAs in the hippocampus of adult mice causes impaired long-term memory performance. In addition, we found that CAMTA knock-down in cultured mouse hippocampal neurons causes impaired dendrite growth. Dendrites are the major site of synaptic input and signal integration. Their morphology thus has a major influence on the functional properties of neurons and impacts on cognitive function. Based on our unpublished findings we thus suggest that CAMTA proteins mediate the formation of long-term memories via transcriptional control of neuronal morphology. In this proposal we will use loss-of-function and gain-of-function approaches in mouse hippocampal neurons in vitro and in the mouse hippocampus in vivo to study the role of mammalian CAMTA proteins in dendrite and dendritic spine morphogenesis and in the formation of long-term memories. In addition, we will use unbiased genomic and bioinformatics approaches to identify CAMTA target genes in neurons that mediate the morphological and cognitive CAMTA loss-of-function phenotypes. Finally, we will investigate the signaling mechanisms that link synaptic activity to CAMTA transcriptional activity.

• DFG Programme: Research Grants
• Participating Person: Professor Dr. Carlos Bas Orth