Neur1 and Neur2 are required for hippocampus‐dependent spatial memory and synaptic plasticity

Abstract

Neur1 and Neur2, mouse homologs of the Drosophila neur gene, consist of two neuralized homology repeat domains and a RING domain. Both Neur1 and Neur2 are expressed in the whole adult brain and encode E3 ubiquitin ligases, which play a crucial role in the Notch signaling pathways. A previous study reported that overexpression of Neur1 enhances hippocampus-dependent memory, whereas the role of Neur2 remains largely unknown. Here, we aimed to elucidate the respective roles of Neur1 and Neur2 in hippocampus-dependent memory using three lines of genetically modified mice: Neur1 knockout , Neur2 knockout , and Neur1 and Neur2 double knockout (D-KO). Our results showed that spatial memory was impaired when both Neur1 and Neur2 were deleted, but not in the individual knockout of either Neur1 or Neur2. In addition, basal synaptic properties estimated by input-output relationships and paired-pulse facilitation did not change, but a form of long-term potentiation that requires protein synthesis was specifically impaired in the D-KO mice. These results collectively suggest that Neur1 and Neur2 are crucially involved in hippocampusdependent spatial memory and synaptic plasticity.

Muscle-Specific Lipid Hydrolysis Prolongs Lifespan through Global Lipidomic Remodeling

“…Global kin-2 RNAi causes animals to become dumpy and severely bloated ( Figure S3B) and is often associated with reduced locomotor activity. These animals also have a dramatically shortened lifespan that is mirrored in kin-2(ce179) mutant animals ( Figure 1J; Figure S3A; Lee et al, 2014Lee et al, , 2016.…”

“…This is catalyzed by lipolytic enzymes such as ATGL and HSL, both of which are subject to complex environmental and hormonal regulation that is mediated by PKA (Coen and Goodpaster, 2012). In C. elegans, KIN-1, the ortholog of the catalytic PKA subunit, directly phosphorylates ATGL-1 to enhance lipolysis, consequently reducing fat stores (Lee et al, 2014). We therefore used an RNAi-based strategy (kin-2 RNAi) to constitutively activate PKA/KIN-1 and its downstream targets, including ATGL-1 (Lee et al, 2014(Lee et al, , 2016.…”

“…In C. elegans, KIN-1, the ortholog of the catalytic PKA subunit, directly phosphorylates ATGL-1 to enhance lipolysis, consequently reducing fat stores (Lee et al, 2014). We therefore used an RNAi-based strategy (kin-2 RNAi) to constitutively activate PKA/KIN-1 and its downstream targets, including ATGL-1 (Lee et al, 2014(Lee et al, , 2016. In addition, we restricted the RNAi response to muscles by using a C. elegans strain that is sensitive to RNAi exclusively in body wall muscle cells (muscle-restricted RNAi [mrRNAi]), allowing us to address the global effects of enhanced PKA signaling uniquely in a single cell type (Qadota et al, 2007;Yigit et al, 2006).…”

“…In most organisms, lipid abundance is strictly regulated and sensitive to numerous physiological and environmental stimuli. One of the major effectors of lipid homeostasis is cyclic AMPdependent protein kinase (also known as protein kinase A [PKA]) (Lee et al, 2014;Zechner et al, 2012). Mammalian PKA consists of two regulatory subunits (PKAr) bound to two catalytic subunits (PKAc) that together form the inactive tetrameric holoenzyme complex.…”

“…When activated, PKA then phosphorylates ATGL-1, a homolog of mammalian ATGL, enhancing its lipolytic activity on the surface of lipid droplets. This enzyme is the rate-limiting step in triglyceride hydrolysis, and its activation results in generation of free fatty acids (FFAs) to maintain energy resources during periods of starvation (Lee et al, 2014).…”