Biomedical Engineering Reference
In-Depth Information
9.1 Diffusion as a Computational Operator
Diffusion is a fundamental process in nature and a key mechanism in biology. At the
body level, diffusion governs the exchange of gases and nutrients in our tissues, but
if we zoom into the cell or at the subcellular level, we can observe that diffusion is
fully involved in regulating cell physiology by driving the motion of organelles and
molecules within the cytoplasm as well as that of macromolecules in the membrane
bilayer. When the organelles or the molecules experiencing diffusion have an
informational role, then diffusion becomes a key process shaping information
content and transfer. At the synapse, this is the case for (1) synaptic vesicles
(SVs), small organelles storing and releasing neurotransmitter in a quantal fashion
by regulated exocytosis; (2) neurotransmitter molecules released into the synaptic
cleft that, based on the dynamics of release, will bind to postsynaptic receptors, but
also diffuse out in the extracellular space, carrying their message through the tissue
volume; and (3) neurotransmitter receptors that undergo both trafficking between a
membrane-exposed pool and an intracellular “inactive” pool, as well as diffusion in
the plane of the membrane between synaptic and extrasynaptic domains (Fig.
9.1
).
From the ensemble of these parallel processes that are layered across the serial
sequence of synaptic events, a new multilayer architecture of synaptic transmission
and plasticity emerges with higher complexity and computational abilities.
9.2 Synaptic Vesicle Pools and Superpool: Synaptic Vesicle
Diffusion, Trafficking, and Sharing
Presynaptic terminals contain many SVs, small organelles (40-50 nm diameter) of
surprisingly homogeneous size that store and release a discrete amount of small
neurotransmitter molecules (e.g., acetylcholine, glutamate, GABA; about 5,000-
10,000 molecules/vesicle). SVs are clustered within the terminal and contact the
presynaptic membrane at the active zone, a specialized area where exocytosis
preferentially occurs. Such SV clusters, together with SV recycling mechanisms,
allow nerve terminals to faithfully convert action potentials into neurotransmitter
secretion over a large firing range.
On a morphological basis, ultrastructure of central synapses shows that a limited
number of SVs are physically docked to the active zone, while the majority of SVs
is distributed in clusters that fill the terminal at various distances from the active
zone. However, on a functional basis, SVs can be divided into “functional pools”
that do not have a close morphological correspondence. On the basis of patch-
clamp electrophysiology and fluorescent reporters of SV cycling (see below), there
is a large consensus on the existence of three SV pools that are characterized by
distinct functions and, possibly, molecular features of SVs. Synaptic vesicles
docked to the active zone and characterized by an already assembled fusion
complex (composed of SNARE proteins, complexins, and Ca
2+
sensor) are primed
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