Editors' ChoiceNeuroscience

Remembering About Cyclin E?

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Sci. Signal.  25 Oct 2011:
Vol. 4, Issue 196, pp. ec296
DOI: 10.1126/scisignal.4196ec296

Cyclins bind to and activate their cognate cyclin-dependent kinases (Cdks) to regulate progression through the cell cycle. For instance, cyclin E binds to and activates Cdk2 to promote the transition from G1 to S phase. Thus, it seems counterintuitive that cyclin E is abundant in postmitotic neurons. After confirming its abundance in adult mouse brain, Odajima et al. showed that cyclin E abundance in adult brain was comparable to that in embryonic brain, whereas little was apparent in other adult organs composed of nonproliferating cells. Mass spectrometric analyses of cyclin E1–associated complexes purified from the brains of adult and embryonic mice revealed Cdk2 in complexes from embryonic brain, whereas complexes from adult brain were enriched in the Cdk-related protein Cdk5 and the Cdk inhibitor p27Kip1. The cyclin E1–Cdk5 complex was catalytically inactive, and experiments in which increasing amounts of cyclin E were coexpressed in 293T cells with Cdk2 and its activator p35 indicated that cyclin E competed with p35 for Cdk5 binding. Acute deletion of cyclin E decreased the density of puncta containing colocalized Synapsin I (a presynaptic protein) and PSD95 (a postsynaptic protein) and the amplitude and frequency of miniature excitatory postsynaptic currents in postmitotic cultured neurons, and it decreased dendritic spine density in hippocampal slices. Cdk5 overexpression phenocopied cyclin E loss, whereas Cdk5 knockdown (or dominant-negative Cdk5) reversed synaptic deficits in neurons without cyclin E. Cyclin E–deficient adult mouse brains showed increased phosphorylation (indicating inhibition) of the Cdk5 substrate Wave1, a protein that promotes dendritic spine maturation, and decreased phosphorylation and surface abundance of the NMDA-type glutamate receptor NR1 subunit (consistent with Cdk5’s inhibition of NMDA receptor assembly). Hippocampal neurons from cyclin E–deficient brains showed decreases in spine volume, spontaneous synaptic activity, and amplitude of NMDA-dependent currents. Moreover, mice lacking brain cyclin E showed impaired NMDA receptor–dependent long-term potentiation of synaptic transmission and impaired spatial learning and memory. Thus, neuronal cyclin E appears to play a role in synaptic plasticity and in memory entirely distinct from its role in the cell cycle. Ghose and Shashidhara provide thoughtful commentary.

J. Odajima, Z. P. Wills, Y. M. Ndassa, M. Terunuma, K. Kretschmannova, T. Z. Deeb, Y. Geng, S. Gawrzak, I. M. Quadros, J. Newman, M. Das, M. E. Jecrois, Q. Yu, N. Li, F. Bienvenu, S. J. Moss, M. E. Greenberg, J. A. Marto, P. Sicinski, Cyclin E constrains Cdk5 activity to regulate synaptic plasticity and memory formation. Dev. Cell. 21, 655–668 (2011). [PubMed]

A. Ghose, L. S. Shashidhara, Cyclin beyond the cell cycle: New partners at the synapse. Dev Cell. 21, 601–602 (2011). [PubMed]

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