Abstract
Long-lasting forms of postsynaptic plasticity commonly involve protein synthesis-dependent structural changes of dendritic spines. However, the relationship between protein synthesis and presynaptic structural plasticity remains unclear. Here, we investigated structural changes in cannabinoid-receptor 1 (CB1)-mediated long-term depression of inhibitory transmission (iLTD), a form of presynaptic plasticity that involves a protein-synthesis-dependent long-lasting reduction in GABA release. We found that CB1-iLTD in acute rat hippocampal slices was associated with protein synthesis-dependent presynaptic structural changes. Using proteomics, we determined that CB1 activation in hippocampal neurons resulted in increased ribosomal proteins and initiation factors, but decreased levels of proteins involved in regulation of the actin cytoskeleton, such as ARPC2 and WASF1/WAVE1, and presynaptic release. Moreover, while CB1-iLTD increased ubiquitin/proteasome activity, ubiquitination but not proteasomal degradation was critical for structural and functional presynaptic CB1-iLTD. Thus, CB1-iLTD relies on both protein synthesis and ubiquitination to elicit structural changes that underlie long-term reduction of GABA release.
Highlights
Synaptic plasticity, the ability of synapses to change their strength in response to activity or experience, underlies information storage in the brain
We found that cannabinoid-receptor 1 (CB1)-iLTD in acute rat hippocampal slices was associated with protein synthesis-dependent presynaptic structural changes
We determined that CB1 activation in hippocampal neurons resulted in increased ribosomal proteins and initiation factors, but decreased levels of proteins involved in regulation of the actin cytoskeleton, such as Actin-related protein 2/3 (Arp2/3), and presynaptic release
Summary
The ability of synapses to change their strength in response to activity or experience, underlies information storage in the brain. A good example of a ubiquitous form of long-lasting reduction of transmitter release in the brain is type-1 cannabinoid receptor (CB1)-mediated LTD Endogenous cannabinoids (eCBs) are released upon activity and travel in a retrograde manner to bind presynaptic CB1, a Gi/o-coupled receptor, resulting in CB1-LTD at both excitatory and inhibitory synapses. Induction of long-term eCB-mediated plasticity requires extended (minutes) CB1 activation (Chevaleyre & Castillo, 2003; Chevaleyre et al, 2007; Ronesi et al, 2004). The presynaptic changes downstream CB1 that suppress transmitter release in a long-term manner remain unclear, there is evidence that presynaptic protein synthesis is required (Yin et al, 2006; Younts et al, 2016), but what proteins are synthesized and the precise role of these proteins in CB1-LTD remain unexplored
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