Chronic changes in synaptic activity result in compensatory alterations in AMPA-type glutamate receptors (AMPARs), but the mechanisms underlying this process have not been fully elucidated. Here, we investigate a feedback mechanism that bidirectionally regulates transcription of the AMPAR GLR-1 in response to chronic changes in synaptic activity. We previously found that trafficking mutants with decreased synaptic GLR-1, such as animals with mutations in the kinesin
klp-4 or the deubiquitinating enzyme
usp-46, exhibit increased levels of
glr-1 transcript (1,2). This increase in
glr-1 mRNA is due in part to increased
glr-1 promoter (Pglr-1) activity based on a
glr-1 transcriptional reporter (Pglr-1::gfp).
glr-1 null mutants exhibit similar increases in
glr-1 transcription, suggesting that decreased synaptic GLR-1 is sufficient to trigger the feedback pathway. Increased
glr-1 transcriptional activity could be due to decreased synaptic GLR-1 protein levels or decreased glutamatergic transmission. Thus, we measured Pglr-1 activity in mutants with reduced synaptic activity such as animals with mutations in the presynaptic vesicular glutamate transporter
eat-4/VGLUT or the SV priming protein
unc-13/Munc13, and found similar increases in Pglr-1 activity. These data suggest that chronic reduction of synaptic activity is sufficient to trigger the feedback pathway. We next tested whether increased GLR-1 levels or activity could repress
glr-1 transcription. We found that
unc-11/AP180 clathrin adaptin endocytic mutants, which accumulate synaptic GLR-1 (3), exhibit decreased
glr-1 transcription. Animals with increased GLR-1 signaling, such as animals expressing a dominant-active version of the receptor (GLR-1(A/T)) or animals with mutations in plasma membrane glutamate transporters,
glt-1;
glt-3, also exhibit decreased
glr-1 transcription, suggesting that the feedback mechanism is bidirectional. Investigation of signaling pathways that may mediate the synapse to nucleus feedback pathway revealed that the CMK-1/CaM kinase I pathway normally functions to repress
glr-1 transcription. Analysis of
cmk-1;
glr-1 double mutants suggests that CMK-1 functions in the same pathway as decreased synaptic activity to regulate
glr-1 transcription. In support of this, we found that the subcellular distribution of GFP-tagged CMK-1 shifts from the nucleus to the cytoplasm in
glr-1 mutants. Together, our results reveal a compensatory feedback mechanism where changes in synaptic activity trigger CMK-1 translocation between the nucleus and cytoplasm to regulate
glr-1 transcription. 1. Monteiro et al. (2012) Mol Biol Cell. 2. Kowalski et al. (2011) J Neurosci. 3. Burbea et al. (2002) Neuron.