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 276

9.4 Neurotransmitter Diffusion
While the mechanisms of transmitter release and the functioning of synaptic
receptors have been extensively investigated, the dynamics of neurotransmitter
diffusion in the synaptic cleft has received less attention. Indeed, it was assumed
that, after the synaptic release, the neurotransmitter in the cleft would reach a
supersaturating concentration, thus representing an all-or-none mechanism.
In contrast, an increasing body of evidence has revealed that the fine modulation
of the spatiotemporal profile of neurotransmitter concentration significantly
impacts on the amplitude and duration of the unitary postsynaptic signals, being
an important determinant for synaptic transmission. In addition, it has also been
shown that neurotransmitter released at a given synapse can diffuse and activate
neighboring synapses representing an efficient mechanism for synaptic cross talk.
In this section, we will review the role of neurotransmitter diffusion in modulating
and coordinating the synaptic function.
9.4.1 Estimating the Dynamics of Neurotransmitter
Diffusion in the Synaptic Cleft
To date, the direct measurement of the neurotransmitter concentration profile in the
synaptic cleft remains a major challenge. Typically, at central synapses, the width
of synaptic cleft is ~20 nm, thus precluding the placement of a measuring device
within the synapse to monitor the agonist time course. Due to this limitation, the
current knowledge of the neurotransmitter dynamics is mainly derived from indi-
rect measurements that infer the synaptic neurotransmitter waveform by analyzing
the susceptibility of the postsynaptic response to pharmacological agents (Barberis
et al. 2011 ). This approach is based on the concept that the degree of postsynaptic
receptor block by competitive blockers closely depends on the concentration profile
of neurotransmitter in the cleft: indeed, strong synaptic neurotransmitter exposures
will overcome the current block by displacing the competitive blockers (generating
mild current block), while weak synaptic exposures will determine a more pro-
nounced current block. Thus, by estimating the degree of synaptic current reduction
induced by competitive blockers, it is possible to infer the neurotransmitter wave-
form in the synaptic cleft that elicits synaptic current. This approach, referred as
“deconvolution,” consistently revealed that, after the vesicle release, the neuro-
transmitter concentration peaks in the cleft at 1-3 mM and decays exponentially
with main time constant of ~0.1 ms (Clements et al. 1992 ; Clements 1996 ;
Diamond and Jahr 1997 ; Mozrzymas et al. 1999 ; Overstreet et al. 2003 ; Barberis
et al. 2004 , 2005 ; Beato 2008 ).
Another strategy to study the spatiotemporal profile of neurotransmitter synaptic
concentration exploits computer model simulations that simulate the neurotrans-
mitter diffusion by using Fick's equation solved for boundary conditions reflecting