Abstract
Neurons use a variety of mechanisms to homeostatically regulate neural network activity in order to maintain firing in a bounded range. One such process involves the bi-directional modulation of excitatory synaptic drive in response to chronic changes in network activity. Down-scaling of excitatory synapses in response to high activity requires Arc-dependent endocytosis of glutamate receptors. However, the temporal dynamics and signaling pathways regulating Arc during homeostatic plasticity are not well understood. Here we determine the relative contribution of transcriptional and translational control in the regulation of Arc, the signaling pathways responsible for the activity-dependent production of Arc, and the time course of these signaling events as they relate to the homeostatic adjustment of network activity in hippocampal neurons. We find that an ERK1/2-dependent transcriptional pathway active within 1–2 h of up-regulated network activity induces Arc leading to a restoration of network spiking rates within 12 h. Under basal and low activity conditions, specialized mechanisms are in place to rapidly degrade Arc mRNA and protein such that they have half-lives of less than 1 h. In addition, we find that while mTOR signaling is regulated by network activity on a similar time scale, mTOR-dependent translational control is not a major regulator of Arc production or degradation suggesting that the signaling pathways underlying homeostatic plasticity are distinct from those mediating synapse-specific forms of synaptic depression.
Highlights
Homeostatic control mechanisms are prevalent in biological systems and are vital for maintaining physiological parameters within a preferred range (Davis, 2006)
We find that under basal conditions, Arc mRNA, measured by quantitative PCR, is acutely sensitive to ongoing transcription such that its levels rapidly decline following transcriptional blockade with actinomycin D (ActD) with an mRNA half-life of ∼45 min (Figures 1B,G)
In this study, we investigated the dynamics of a homeostatic signaling pathway induced by network activity in hippocampal neurons
Summary
Homeostatic control mechanisms are prevalent in biological systems and are vital for maintaining physiological parameters within a preferred range (Davis, 2006). One well-characterized form of homeostatic plasticity is the scaling of excitatory synapses in response to chronic changes in network activity, which produces a proportional change in strength across the majority of synapses onto a neuron (Turrigiano et al, 1998). This synaptic scaling occurs bidirectionally to counterbalance the effects of altered network activity and is a form of negative feedback. During periods of low activity, Arc levels drop, which allows the accumulation of synaptic glutamate receptors This up- or down-regulation of glutamate receptors produces compensatory changes in excitatory drive that are thought to help restore firing rates to their preferred levels. Consistent with a negative feedback function for Arc in regulating neural activity, global deletion of Arc in mice leads to network hyperexcitability and seizures (Peebles et al, 2010)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
