Neuroscience, MAPKs, MKPs, CNS, synaptic maturation, glial proliferation.

A role for mitogen-activated protein kinases (MAPKs) is well established in physiological cell function as well as in certain disease states¹. Recently, there has been growing interest in the signalling systems which control MAPK function, especially the attenuation of their activity.  One family of proteins that contribute to this process is the mitogen-activated protein kinase phosphatases (MKPs)². There is significant interest in MKPs especially in relation to their role in development, the immune system and cancer^3,4.  However, there is a significant gap in our knowledge in relation to their function in the central nervous system (CNS).  However we have recently shown that Dusp4 deletion results in altered synaptic activity leading to impaired synaptic plasticity and learning and memory⁵. Furthermore we have generated preliminary data showing reduced neurite growth and glial proliferation in primary cultures and that altered synaptic transmission may be due to altered synaptic vesicule distribution. 

Hence, we hypothesise that MKP-2 is important in CNS development and function.  Based on our findings we propose to further investigate the role of astrocytes and microglia on neuronal development and identify how MKP2 deletion results in altered synaptic vesicule distribution. Techniques well established in our laboratories will be used to further explore MKP-2 function in the CNS, specifically 1) to examine the role of reduced glial proliferation in altered hippocampal function and 2) to determine how synaptic vesicular distribution is modulated by MKP2 deletion. Overall this project will lead to a better understanding of the role of MKP-2 in the CNS and its function in synaptic development and maturation

Neuronal culture, acute brain slices, electrophysiology, Ca²⁺ imaging, immunohistochemistry, qPCR & western blotting.

1. Harper & Wilkie Exp Op Ther Targets (2003) 7:187-200

2. Caunt  & Keyse  (2012), FEBS Journal, 280:489-504

2. Al-Mutairi et al., PLoS Pathog (2010) 6:e1001192. 

3. Lawan et al., J Biol Chem (2011) 286:12933-43.