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 278

concerns the definition of “effective neurotransmitter concentration.” According to
classical “equilibrium” pharmacology, the relative current amplitude is univocally
determined by the agonist concentration: conversely, in nonequilibrium conditions,
the degree of receptor activation depends on both the concentration and the
duration of the agonist exposure. For instance, 1-3 mM GABA is supersaturating
in equilibrium conditions, but is no longer saturating if applied for only 100

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s.
Another consequence of “nonequilibrium conditions” is that the amplitude of
synaptic current is extremely susceptible to the duration of the neurotransmitter
exposure. The experimental evidence of this latter point has been obtained by using
polymers such as dextran that, by increasing the viscosity of the extracellular
medium, slows down neurotransmitter diffusion thereby prolonging the presence
of neurotransmitter in the synaptic cleft. In these conditions of reduced neurotrans-
mitter clearance, indeed, the peak amplitude of synaptic current both at gluta-
matergic and GABAergic synapses significantly increased, confirming the general
idea that the brief synaptic exposure represents a limiting factor for the activation of
postsynaptic receptors (Min et al. 1998 ; Perrais and Ropert 2000 ; Barberis
et al. 2004 ).
Nonequilibrium conditions have also been demonstrated to influence the kinetics
of synaptic current decay. GABA A receptors (GABA A Rs) require the binding of
two agonist molecules to fully activate. However, it has been proposed that
GABA A Rs can open in the monoliganded state mediating currents decaying almost
one order of magnitude faster than that elicited in the double bound state (Macdon-
ald et al. 1989 ; Jones et al. 1995 ; Petrini et al. 2011 ). By using model simulations,
we examined the impact of these two GABA A R activation modes at the synapse and
found that “synaptic-like” GABA exposures favored the GABA A R activation in the
singly bound state, especially at the periphery of the postsynaptic disk where the
GABA concentration is almost one order of magnitude lower than that observed in
front of the releasing site (Petrini et al. 2011 ). In these conditions, the duration of
the neurotransmitter exposure can efficiently tune the decay kinetics of synaptic
current by modulating the ratio of singly bound vs. doubly bound activation of
GABA A R.
Another “receptor gating feature” that can be unmasked in nonequilibrium
conditions concerns the specific role of GABA A R desensitization. It is well
established that the decay time of GABAergic currents is heavily shaped by
desensitization (Jones et al. 1995 ; Jones and Westbrook 1998 ). Indeed, after the
agonist removal, the current deactivation is prolonged by the time needed to exit
from desensitized state(s). Thus, the length of agonist exposure modulates the
degree of receptor desensitization accumulation, hence controlling the duration of
synaptic currents (Jones et al. 1995 ; Petrini et al. 2011 ). The kinetics of currents
mediated by glutamatergic kainate receptors has also shown clear dependence upon
the transmitter exposure time. Indeed, although currents mediated GluK2/GluK5
heteromeric receptors show fast decay kinetics when elicited by “long” (100 ms)
pulses of saturating glutamate, they display a singnificantly slower deactivation
time course upon “brief” (~1 ms) glutamate exposures (Barberis et al. 2008 ). The
molecular mechanism of this relation between glutamate exposure and current