Ashlyn Spring and Sam Trammell Will Present their Research on Wednesday, 5/13/15
Fibroblast Growth Factor Receptor signaling and Src Family Kinase activity gate homeostatic synaptic plasticity
Synapses undergo many stresses and plastic changes throughout the life of an organism. Homeostatic mechanisms respond to these stresses and maintain synaptic activity within a physiologically favorable range. When faced with a reduction in postsynaptic glutamate receptor activity, the Drosophila neuromuscular junction (NMJ) homeostatically compensates by sending a retrograde signal to the presynaptic nerve. This signal triggers an increase in the number of synaptic vesicles released from the presynaptic terminal during an action potential. One of the least well understood aspects of this process is how postsynaptic systems drive production of homeostatic retrograde signals. We have identified several factors that regulate homeostatic synaptic plasticity in the postsynaptic muscle through an RNAi- and electrophysiology-based screen. This screen revealed that C-terminal Src Kinase (Csk) and the fibroblast growth factor receptor (FGFR) Heartless (Htl) are required for homeostatic compensation at the NMJ.
Work with Csk mutant alleles shows that Csk is required for the long-term maintenance of synaptic homeostasis, but not the rapid induction of this process. Csk phosphorylates and inactivates Src Family Kinases (SFKs), of which there are two in Drosophila: Src64B and Src42A. Overexpression and suppression experiments indicate that the homeostatic defects of Csk mutants are due to elevated SFK activity in the postsynaptic muscle. Immunostaining reveals that Csk mutants have altered NMJ localization of the neural cell adhesion molecule (NCAM) ortholog Fasciclin II (FasII). We examined a potential role for FasII in homeostatic plasticity and found that increasing FasII levels partially impairs this process. Additionally, reducing FasII in a Csk mutant background restores homeostatic compensation, suggesting that Csk and FasII may regulate homeostatic compensation through a common pathway.
We show that Htl is required in the postsynaptic muscle for the long term maintenance, but not the rapid induction, of homeostatic signaling. Htl is known to activate Src64B, and we show that Src64B is required for homeostasis in the postsynaptic muscle and link Src64B and Htl/FGFR signaling in the context of homeostatic compensation. FasII has been implicated as a regulator of Htl activity in Drosophila, which is supported by our observation that FasII genetically interacts with Htl during homeostatic compensation. Collectively, these data shed light on several postsynaptic factors that may work in concert to regulate the production of a homeostatic retrograde signal.
Nicotinamide Riboside is Uniquely Bioavailable In Vivo
Nicotinamide riboside is a recently discovered NAD precursor vitamin with unique activities in protection against metabolic and neurodegenerative conditions. Though nicotinamide riboside has been administered through multiple routes, it has not been established whether it achieves different or superior bioavailability in any target tissue with respect to the other NAD precursor vitamins, nicotinic acid and nicotinamide. Moreover, because enzymatic digestion of nicotinamide riboside can produce the other two NAD precursor vitamins, it is not clear whether nicotinamide riboside acts as a unique chemical entity or whether there are nicotinamide riboside-specific biomarkers. Here we show that nicotinamide riboside exhibits superior oral availability in mouse despite its metabolism to nicotinamide prior to absorption.