Activity-dependent AIDA-1 nuclear signaling regulates nucleolar numbers and protein synthesis in neurons

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Abstract

Neuronal development, plasticity and survival require activity-dependent synapse-to-nucleus signaling. Most studies implicate an activity-dependent regulation of gene expression in this phenomenon. However, little is known about other nuclear functions that are regulated by synaptic activity. Here we show that a newly identified component of rat postsynaptic densities (PSDs), AIDA-1d, can regulate global protein synthesis by altering nucleolar numbers. AIDA-1d binds to the first two postsynaptic density–95/Discs large/zona occludens-1 (PDZ) domains of the scaffolding protein PSD-95 via its C-terminal three amino acids. Stimulation of NMDA receptors (NMDARs), which are also bound to PSD-95, results in a Ca2+-independent translocation of AIDA-1d to the nucleus, where it couples to Cajal bodies and induces Cajal body–nucleolar association. Long-term neuronal stimulation results in an AIDA-1–dependent increase in nucleolar numbers and protein synthesis. We propose that AIDA-1d mediates a link between synaptic activity and control of protein biosynthetic capacity by regulating nucleolar assembly.

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Figure 1: Characteristics of AIDA-1d.
Figure 2: Cellular distribution of eGFP–AIDA-1d.
Figure 3: Mechanism of AIDA-1d nuclear translocation.
Figure 4: AIDA-1d binds PSD-95 and is in a complex with NR1.
Figure 5: The AIDA-1d C-terminal 3 amino acids are required for an interaction with PSD-95 and for a synaptic enrichment, but not for nuclear shuttling.
Figure 6: AIDA-1d expression and neuronal activity results in Cajal body (CB)-nucleolar association.
Figure 7: Activity- and AIDA-1–dependent increase in nucleolar numbers.
Figure 8: AIDA-1 mediates the activity-dependent increase in protein synthesis.

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Acknowledgements

We thank A. Lamond (Univ of Dundee) and E. Tan (Scripps Institute) for antibodies to p80-coilin and S. De Souza for PSD-95 plasmid. This work was supported by grants from the US National Institutes of Health (to E.B.Z., R01 MH67229, and B.A.J., K01 MH073759-02).

Author information

The study was conceived and carried out in its majority by B.A.J. Purification of PSDs, NLS screen and AIDA-1 constructs were performed by B.A.J and B.D.F. Additional AIDA-1 constructs and viruses were made by L.K. The experiments performed are the result of extensive discussions with and mentorship of E.B.Z. The manuscript was written by B.A.J. and E.B.Z.

Correspondence to Bryen A Jordan.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Alignment of AIDA-1 isoform sequences. (PDF 1274 kb)

Supplementary Video 1

Primary hippocampal neurons grown on 6-cm plates containing coverslip bottoms and expressing eGFP–AIDA-1d were placed into an environmental chamber (37 °C and 5% CO2, Carl Zeiss) for 2 h to equilibrate and imaged every 20 s. (MOV 1895 kb)

Supplementary Video 2 (MOV 1044 kb)

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