1 are upregulated by the activation of Elkl and CREB and are specifically connected with the protein synthesis-dependent stage of memory consolidation.69,70 An important aspect of this Ras-ERK signaling pathway is that it is diffusive, allowing downstream effects at locations relatively distant to the initial site of activation. Furthermore, this pathway may be required to recruit AMPARs from distal sites to synapses. AMPAR exocytosis several micrometres away from potentiated synapses is prevented by blocking Ras-ERK signaling, suggesting it initiates AMPAR insertion

at relatively distant dendritic regions, ready for incorporation into the synapse.71 The PKC family of serine/threonine kinases participate at Inhibitors,research,lifescience,medical different stages in the induction and maintenance of plasticity. LTP expression and memory formation Inhibitors,research,lifescience,medical require PKC activity72,73 and activation of PKC can rescue LTP prevented by NMDAR blockade.74 Direct PKC phosphorylation of Ser816 and Ser818 in GluA1 mediates activity-dependent insertion during LTP75 by enhancing binding of GluA1 to the actin cytoskeletal linker protein, 4. IN.76 PKC isoforms generally require both calcium and diacylglycerol for activation,

Pazopanib chemical structure although atypical PKCs (ζ, and ι / λ isoforms) require neither.77 Of these, the Inhibitors,research,lifescience,medical constitutively active atypical PKC isoform protein kinase M zeta (PKMζ is of particular interest and has been the focus of intensive research. PKMζ has been dubbed the “memory molecule” since it is proposed to be both necessary and sufficient to maintain potentiated synapses.78,79 In electrophysiology experiments perfusion of PKMζ in a patch pipette has been reported to be sufficient to produce LTP in slices78 and inhibition of PKMζ Inhibitors,research,lifescience,medical erases memory and reverses LTP in vivo.80 Intriguingly, inhibition of PKMζ does not block LTP induction. Rather, it prevents maintenance of LTP and Inhibitors,research,lifescience,medical can erase established memories without preventing formation of new short-term memories.81 Subsequent studies have suggested that the mechanism of action of PKMζ appears to involve regulation of the GluA2 interacting proteins N-ethymaleimide-sensitive factor (NSF) and PICK1, although the exact mechanisms

involved, and the targets of PKMζ which mediate its roles in synaptic plasticity also remain unclear.82,83 It should be noted, however that these data remain controversial since they rely mainly on the use of the zeta inhibitory peptide (ZIP) and issues have been raised about the selectivity of ZIP between different PKC isoforms.84 Phosphorylation and LTD As for AMPAR exocytosis and LTP, the interplay between synaptic phosphorylation and dephosphorylation is central to regulated AMPAR endocytosis and LTD. For example, PKA is located at the postsynaptic density by the anchoring protein AKAP150, which binds directly to PSD-95. Blocking these interactions causes deficits in synaptic transmission85 and inhibits NMDARdependent AMPAR endocytosis and LTD.