For example, CaMKIIβ mRNA is strikingly restricted to the soma and proximal dendrites (Martone et al., 1996) and its protein expression

is dynamically regulated in homeostatic plasticity (Thiagarajan et al., 2002). AMPA-induced AMPAR internalization also occurs primarily in soma and proximal dendrites of hippocampal neurons (Biou et al., 2008). Together, these findings suggest a role of the proximal dendrite as a homeostatic domain and also emphasize the importance of specifying the dendritic subregion studied in homeostatic plasticity. This caveat may explain, at least in part, discrepancies in the literature regarding AMPAR subunits involved in homeostatic regulation. The function of Plk2 in vivo has been GSI-IX explored previously using knockout animals, but not examined in synaptic plasticity (Inglis et al., 2009 and Ma et al., 2003a). We used a dominant-negative transgenic approach to address potential functional redundancy by binding to all shared targets of the Plk subfamily and inactivating them by sequestration. However, it is highly likely that Plk2 is the relevant polo family kinase involved in activity-dependent homeostatic synaptic downregulation, based on the similar effect of Plk2 RNAi on spines in cultured neurons to DN-Plk2 expressed in TG animals, the absence of Plk1 and Plk4 expression in normal brain tissue (Winkles and Alberts,

2005), and lack of effect of Plk3 RNAi on PTX-induced homeostatic plasticity in any of our assays. The precise function of Plk3 in brain is unknown, selleckchem but as this kinase was originally identified as an FGF-inducible of factor, Plk3 may be responsive to neurotrophic or other growth factor stimulation. DN-Plk2 animals exhibited increases in RasGRF1 and SPAR protein levels, similar to expression of DN-Plk2 in dissociated neuron culture. These effects were accompanied by elevated levels

of active Ras and several phenotypes consistent with previously described consequences of Ras overactivity including increased ERK activation, slightly enlarged cortex (probably due to neuronal hypertrophy) (Heumann et al., 2000), higher spine density (Arendt et al., 2004), and elevated GluA1 expression (Kim et al., 2003). Perhaps the most striking observation was that TG forebrains had nearly undetectable levels of active Rap1 or Rap2. Thus, Plk2 appears to be critically required for Rap activation in the brain, at least under basal conditions of normal ongoing activity. It is nevertheless probable that Plk2-independent pathways to Ras and Rap regulation exist, particularly under conditions of acute plasticity or stimulation (Woolfrey et al., 2009). Ras signaling plays critical roles in learning and memory (Mazzucchelli and Brambilla, 2000). Somewhat surprisingly, DN-Plk2 mice exhibited normal working memory and no deficit in acquisition of the Morris water maze task.