Editors' ChoiceNeuroscience

Memories of Degradation

Science's STKE  18 Mar 2003:
Vol. 2003, Issue 174, pp. tw107-TW107
DOI: 10.1126/stke.2003.174.tw107

Activity-dependent changes in structure and function of neuronal synapses are thought to provide the molecular basis for learning and memory in the brain. Attention has focused on requirements of transcription and translation for such synaptic changes, but Ehlers describes experiments indicating that ubiquitin-dependent protein degradation also contributes to remodeling at the postsynaptic density (PSD) (where neurotransmitter receptors are clustered with various signaling proteins). Pharmacological treatments of cultured rat cortical neurons that increased synaptic activity caused increases in the abundance of some proteins at isolated PSDs but also caused decreases in the abundance of others. Pharmacological inhibition of synaptic activity caused reciprocal changes (increasing, for example, the abundance of proteins that were lost at activated synapses). Pulse-chase analysis of protein turnover showed that changes in turnover accounted for some of the alterations noted above. Protein degradation can be acutely controlled by ubiquitination, which targets a protein for degradation by the proteasome. Ehlers found that three postsynaptic scaffold proteins (proteins that organize clusters of signaling molecules at synapses) underwent increased ubiquitination in cultured neurons in which synaptic activity was stimulated and showed decreased ubiquitination when isolated from neurons in which synaptic activity was blocked. These changes were correlated with a reciprocal switch in coupling of NMDA-type glutamate neurotransmitter receptors to stimulation of CREB (the cyclic AMP response element-binding protein) or mitogen-activated protein kinases, respectively. These alterations in receptor coupling to downstream signaling pathways were prevented when protein degradation was blocked by treatment of cells with inhibitors of the proteasome. Together the results suggest that long-term changes in synaptic activity can be brought about through regulated degradation of key organizing molecules in the synapse.

M. D. Ehlers, Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system. Nature Neurosci. 6, 231-242 (2003). [Online Journal]