title: Dicer and eIF2c are enriched at postsynaptic densities in adult mouse brain and are modified by neuronal activity in a calpain-dependent manner.
abstract: We have hypothesized that small RNAs may participate in learning and memory mechanisms. Because dendritic spines are important in synaptic plasticity and learning, we asked whether dicer, the rate-limiting enzyme in the formation of small RNAs, is enriched within dendritic spines. In adult mouse brain, dicer and the RNA-induced silencing complex (RISC) component eIF2c were expressed in the somatodendritic compartment of principal neurons and some interneurons in many regions, and dicer was enriched in dendritic spines and postsynaptic densities (PSDs). A portion of dicer and eIF2c were associated with each other and with fragile X mental retardation protein (FMRP), as assessed by co-immunoprecipitation. Calpain I treatment of recombinant dicer or immunopurified brain dicer caused a marked increase in RNAse III activity. Purified PSDs did not exhibit RNAse III activity, but calpain caused release of dicer from PSDs in an enzymatically active form, together with eIF2c. NMDA stimulation of hippocampal slices, or calcium treatment of synaptoneurosomes, caused a 75 kDa dicer fragment to appear in a calpain-dependent manner. The findings support a model whereby acute neuronal stimulation at excitatory synapses increases intracellular calcium, which activates calpain, which liberates dicer and eIF2c bound to PSDs. This supports the hypothesis that dicer could be involved in synaptic plasticity.
authors.affiliation: University of Illinois at Chicago, UIC Psychiatric Institute, Chicago, Illinois, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Lugli
authors.forename: John
authors.initials: J
authors.lastname: Larson
authors.forename: Maryann E
authors.initials: ME
authors.lastname: Martone
authors.forename: Ying
authors.initials: Y
authors.lastname: Jones
authors.forename: Neil R
authors.initials: NR
authors.lastname: Smalheiser
mesh_terms: D000818:Animals; D060565:Argonaute Proteins; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002154:Calpain / Q000378:metabolism* / Q000494:pharmacology; D048429:Cell Size; D003712:Dendrites / Q000378:metabolism; D039642:Eukaryotic Initiation Factors / Q000378:metabolism*; D051860:Fragile X Messenger Ribonucleoprotein 1; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000378:metabolism; D043244:Ribonuclease III / Q000737:chemistry / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D060565:Argonaute Proteins; D002118:Calcium; D002154:Calpain; D039642:Eukaryotic Initiation Factors; D051860:Fragile X Messenger Ribonucleoprotein 1; D016202:N-Methylaspartate; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D016601:RNA-Binding Proteins; D043244:Ribonuclease III; C115848:AGO1 protein, human; C497684:Fmr1 protein, mouse