MkI Transcription Cofactors Regulate Structural Plasticity in Hippocampal Neurons

Expressed throughout the central nervous system, the myocardin-related, megakaryoblastic acute leukemia 1 and 2 (MkI1/2) are transcriptional cofactors that can be found tethered in the cytoplasm to monomeric actin but on synaptic activation translocate to the nucleus and associate with transcription factors such as serum response factor (SRF) to regulate expression of structural genes. This implies a potential role for Mk Is in linking synaptic activity, through gene-expression control, to neuronal structural plasticity. Here, we present evidence that Mk Is, particularly MkI2, are powerful regulators of neuronal structure in vitro. Moreover, using the passive avoidance-conditioning paradigm, we identify learning-associated alterations of neuronal MkI expression that appear to contribute to 2 phases of gene regulation during memory consolidation in the hippocampus. Gene regulation immediately after learning includes Egr2 and may be facilitated by down-regulation of Mk's likely releasing ternary complex factor-regulated SRF activity. The second transcriptional phase occurs later at the 3h postavoidance time point when MkI accumulates in the nucleus of hippocampal neurons and there is enhanced transcription of MkI-dependent structural genes that may contribute to the elaboration of new, memory-associated synapses known to appear over the subsequent 3-h period.