Complexity and Computation at the Synapse: Multilayer Architecture and Role of Diffusion in Shaping Synaptic Activity and Computation - Bioinspired Approaches for Human-Centric Technologies - page 285

lateral mobility of receptors at synapses is strongly influenced by interactions with
scaffold proteins that limit the receptor diffusion by acting as “diffusion traps”. At
glutamatergic synapses, several studies have highlighted that long-term potentia-
tion (LTP) is largely dictated by lateral diffusion-mediated dendritic redistribution
of AMPA receptors that are likely stabilized at synapses due to increased inter-
action with scaffold proteins at the glutamatergic postsynaptic density (PSD)
(Makino and Malinow 2009 ; Petrini et al. 2009 ; Opazo et al. 2010 , 2012 ). However,
it has not been established yet whether after plasticity induction the increased
AMPA receptor anchoring occurs through either increased receptor affinity or
higher availability of “anchoring slots.” Bats et al. ( 2007 ) demonstrated that the
binding between stargazin (transmembrane AMPA receptor regulatory protein
(TARP)) and PSD95, the main component of glutamatergic density, is crucial for
the immobilization of AMPA receptors at synapses. More recently, it has been
shown that the stargazin-PSD95 interaction, if favored by the stargazin phosphory-
lation by the CaMKII kinase (Opazo et al. 2010 ), suggesting that, during LTP,
CaMKII activity promotes the stabilization of AMPAR-stargazin onto preexisting
“PSD95 slots” (Opazo et al. 2012 ).
Besides interaction with scaffold proteins, other “diffusive mechanisms” have
been described to play an important role of AMPA receptor stabilization at synap-
ses. Petrini et al. ( 2009 ) demonstrated that a local the presence of endocytic zones
(EZs) adjacent to glutamatergic synapses establishes a “local receptor recycling”
that maintains a pool of mobile receptors at synapses crucial for the accumulation of
receptors at synapses during synaptic plasticity. Furthermore, EZs, by reversibly
trapping AMPA receptors, act as diffusional barriers limiting the dispersion of
receptors from glutamatergic synapses.
At GABAergic synapses, the role of diffusion on the changes of synaptic
strength has been mainly analyzed during long-term depression (LTD). Sustained
neuronal activity, indeed, has been demonstrated to decrease inhibitory synaptic
currents due to reduced GABAA receptor and gephyrin clustering (Bannai
et al. 2009 ). In the same study, this observation was associated with increased
mobility and decreased confinement of GABAA receptor at synapses. Similar
results are shown in Muir et al. ( 2010 ) where activation of glutamatergic synapses
(with consequent calcium entry through NMDA receptors) led to mobilization and
dispersal of GABAA receptors at GABAergic synapses. Interestingly, these two
studies highlight the role of the phosphatase calcineurin in this form of synaptic
depotentiation. In particular, Muir et al. ( 2010 ) found that the lower interaction of
GABA receptors at GABAergic PSD and its consequent higher synaptic lateral
diffusion is due to the dephosphorylation of the residue Serine 327 on the 2 subunit

of GABAA receptors, a residue already reported to interfere with GABAA receptor
stability at synapses (Wang et al. 2003 ). It is interesting to point out that neuronal
activity with consequent increase of intracellular [Ca ++ ] immobilizes AMPA recep-
tors (Borgdorff and Choquet 2002 ) while increasing the diffusion of GABAA
receptors. This opposite effect may play an important functional role in the coor-
dination of the activity of excitatory and inhibitory systems. Indeed, as LTP and
LTD are associated to immobilization and mobilization of synaptic receptors,

γ