Biology Reference
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membrane. Another mechanism is modification of the AMPA channel's activity via its
phosphorylation. LTP was found to be associated with phosphorylation of GluR1 on Ser-831
(CaMKII) and on Ser-845 (PKA) [Barria et al., 1997; Derkach et al., 2007]. The longer-
lasting components of LTP require new protein synthesis, gene transcription, regulated
protein degradation, changes in spine morphology and density involving actin cytoskeletal
reorganization. The triggering of the NMDA receptor-dependent form of LTD requires also
Ca
2+
entering the dendritic spine through the NMDA channel, Ca
2+
release from intracellular
stores and PP activity. LTD expression is associated with dephosphorylation of Ser-845
which decreases AMPA receptor channel open probability [Banke et al., 2000]. A loss of
AMPA receptor at the synapse plasma membrane is also observed [Beattie et al., 2000]. The
maintenance of LTD, like the one of LTP, requires protein synthesis and regulated protein
degradation. Long-lasting synaptic plasticity is a widespread phenomenon expressed at
possibly every excitatory synapse, with identical but also different mechanisms compared to
those of the hippocampus.
In initial experiments spinophilin and PP1 have been implicated in the regulation of
AMPA-type glutamate receptor [Yan et al., 1999]. In spinophilin KO mice, whole-cell patch-
clamp recording of dissociated cells showed that the ability of PP1 to regulate AMPA
(medium spiny neurons prepared from the striatum) and NMDA (dissociated hippocampal
neurons) glutamatergic receptor channels, which are highly enriched in dendritic spines is
reduced
[Feng et al., 2000]. AMPA receptor currents were more persistent and the
enhancement of NMDA receptor currents by PP1 inhibitors was attenuated in spinophilin KO
mice. These results suggested that spinophilin by targeting PP1c to AMPA and NMDA
channels promotes their down regulation by dephosphorylation. The laboratory of W. Peti has
recently proposed a model in which a dimer of spinophilin bind via the PDZ domain of one of
its molecule to either the GluR2/GluR3 subunits of AMPA receptor or to the NR1C2' of
NMDA receptor while the second molecule of spinophilin targets PP1c either to
Ser-845 of
GluR1 or to Ser-897 of NR1 (two PKA phosphorylation sites). This organization brings PP1c
in the vicinity of the carboxy-terminal phosphorylation sites in its substrates and allows
catalytic efficiency [Kelker et al., 2007].
Electrophysiological studies in hippocampal slices from spinophilin null mice note
reduced LTD but normal LTP, in agreement with previous observations [Mulkey et al., 1993;
Blitzer et al., 1998; Feng et al., 2000].
On the other hand, studies using mutant neurabin 1
showed that the wild-type neurabin 1/PP1c complex promotes lasting synaptic depression on
LTD stimuli, inhibits LTP and prevents synaptic depression under basal conditions in
hippocampal CA1 neurons [Hu et al., 2006]. The complex stimulates multiple signalling
pathways involved in AMPA receptors subunits (GluR1 and GluR2) trafficking, depending
on the pattern of synaptic activity [Hu et al., 2007]. Studies using neurabin 1 KO mice
provide different evidence. In neurabin 1 KO mice, whole-cell patch clamp studies with
hippocampal CA1 neurons showed that the deletion of the scaffolding protein abolished LTP
whereas LTD was unaltered [Wu et al., 2008]. Moreover, an increased AMPA receptor- (but
not NMDA-) mediated synaptic transmission was observed. Deletion of neurabin 1 regulated
GluR1 phosphorylation in a site-specific manner. Phosphorylation of the main PKA site (Ser-
845) was decreased whereas the one of CaMKII (Ser-831) was unaltered. Neurabin 1 KO
mice showed a deficit in contextual fear conditioning, a form of associative memory, but not
in auditory fear memory [Wu et al., 2008].
