CDK-5 is a cyclin-dependent kinase that acts primarily in the nervous system, where it is involved in multiple aspects of neuronal development, contributes to neurodegeneration, and has recently emerged as a regulator of synaptic plasticity (1,2). We examined the role of CDK-5 in synaptic transmission at the C. elegans neuromuscular junction (NMJ) by testing
cdk-5 mutants for changes in paralysis induced by the acetylcholine (ACh) esterase inhibitor aldicarb. We show here that two independent loss-of-function alleles of
cdk-5,
gm336 and
ok626, are resistant to aldicarb-induced paralysis. Both alleles result in deletions that remove the start codon and are predicted to be molecular nulls. Expression of wild type
cdk-5 cDNA under the cholinergic motorneuron promoter (Punc-17) rescues the decrease in synaptic transmission observed in
cdk-5 null mutants. Furthermore, overexpression of
cdk-5 under the
unc-17 promoter in wild type animals results in increased synaptic transmission. CDK-5 activity is dependent on activation by its binding partner,
p35 (1). Consistent with this, we find that
p35(gm335) loss-of-function mutants are resistant to aldicarb-induced paralysis. In order to identify how CDK-5 is regulating synaptic transmission, we are currently analyzing the effect of
cdk-5 mutations on a panel of fluorescent presynaptic markers. We are also investigating the possibility that CDK-5 may indirectly influence ACh release by regulating neuropeptide secretion. Neuropeptides can modulate ACh release and mutations in neuropeptide processing enzymes, such as the proprotein convertase
egl-3 PC2, are resistant to aldicarb-induced paralysis (3). Preliminary evidence shows that
cdk-5(
gm336);
egl-3(
nr2090) double mutants have rates of aldicarb-induced paralysis that are comparable to either single mutant alone, suggesting that CDK-5 and PC2 act in the same pathway to increase ACh release. We are currently testing other genes involved in neuropeptide processing for genetic interactions with
cdk-5 and directly imaging fluorescently tagged neuropeptides (4) in
cdk-5 mutants. Results from these various experiments will be presented. (1) Dhavan, R. and Tsai, L.H. (2001). Nat. Rev. Mol. Cell. Biol. 2: 749-759. (2)Cheung, Z.H. et. al. (2006). Neuron 50: 13-18. (3) Jacob, T.C. and Kaplan, J.M. (2003). J. Neurosci. 23:2122-2130. (4) Sieberth, D.S. et. al. (2006). Nat Neurosci. 10: 49-57.