Biomedical Engineering Reference
In-Depth Information
and asynchronous components of release compete for the same pool of SVs, the
presence of presynaptic protein isoforms favoring one type or the other of release
indicates that heterogeneity exists between distinct subpopulations of SVs within
the same nerve terminals or among synapses exhibiting a distinct complements of
Ca
2+
channel subtypes and/or SV protein isoforms.
Asynchronous release in inhibitory synapses may play an important role in the
volume control of excitability. Changes in GABA asynchronous release between
specific neurons from human epileptic and non-epileptic tissue have been recently
reported. Interestingly, long-lasting inhibitory PSCs generated by asynchronous
GABA release, occurring with significant delays after trains of action potentials or
in some cases just one action potential, can increase the effectiveness of inhibition.
GABA spillover and GABA concentrations in the interstitial fluid mainly result
from asynchronous release, whose charge as a function of time can provide a more
continuous supply of neurotransmitter to the extracellular space. In this respect,
synapsin knockout mice strongly defective in asynchronous release also lack tonic
inhibition (Farisello et al.
2013
). Interestingly, in central synapses, asynchronous
GABA release apparently allows an inhibitory compensatory tuning proportional to
the extent of presynaptic activity and is markedly increased when synapses are
stimulated with behaviorally relevant high-frequency patterns.
The availability of genetically encoded fluorescent Ca
2+
indicators that speci-
fically target synaptic boutons allows relating the dynamics of Ca
2+
transients with
the dynamics of release. The sensor GCaMP2, for example, has been efficiently
fused to the cytoplasmic end of the SV proteins synaptotagmin or synaptophysin,
thus reporting nerve terminal Ca
2+
transients with high spatial and temporal preci-
sion and a linear response over a wide range of action potential frequencies (Dreosti
et al.
2009
). Moreover, we are currently engineering an array of microbial opsins
(such as the excitatory opsins ChETA and CATCH derivatives of channelrhodopsin
or the inhibitory opsin halorhodopsin; Mattis et al.
2011
; Prakash et al.
2012
)to
target their expression to presynaptic terminals by fusion with the SNARE protein
SNAP-25. A similar targeting strategy has also been applied to the photoswitchable
kainate receptor LiGluK2 (see below) that can be commanded to open and close
(binding and unbinding of the cross-linked azido-glutamate) by illumination with
distinct wavelengths (Szobota et al.
2007
; Gorostiza and Isacoff
2008
). While in the
case of the fast cationic channel ChETA or the Cl
pump halorhodopsin, the
respective inward and outward currents can affect the temporal profile of depolar-
ization and the activation kinetics of voltage-gated Ca
2+
channels, CATCH and
LiGliK2 are directly permeable to Ca
2+
and therefore can directly affect the
intraterminal Ca
2+
concentrations. The use of these targeted tools, together with
genetically encoded targeted Ca
2+
indicators, will soon allow switching from one
mode of release to another one by light to further dissect the mechanisms and
functional roles of spontaneous, synchronous, and asynchronous release.
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