elaborated to describe zinc changes associated with the most important zinc-binding
sites in the synaptic cleft between a mossy fiber terminal and a pyramidal cell of the
hippocampal CA3 area, as previously reported [12]. Assuming that zinc is co-released
with the neurotransmitter glutamate, this model was constructed taking into account
previous studies that include computer simulations of glutamate dynamics in the
synaptic cleft [13–16]. In the zinc model [12], the variation of total cleft zinc changes
is obtained by subtracting two alpha functions, describing zinc release and zinc
uptake. These functions, characterized by rapid climb phases and slower decays, were
determined based on the assumed maximum amplitude and rising time values of cleft
free zinc concentration. The corresponding parameters were defined taking into
account experimental results, from optical and electrophysiological zinc experiments,
reporting cleft zinc changes [17–27].
The process of zinc clearance from the synaptic cleft may include various
actions, such as zinc binding, uptake, and entry into postsynaptic cells. Zinc can
bind to a variety of pre- and/or postsynaptic receptors, voltage-dependent ionic
channels, glutamate transporters expressed in glial cells, and also free molecules in
the cleft medium. One of the most important targets for zinc action is the Nmethyl-D-aspartate (NMDA) receptor-binding site with a high affinity for zinc
[28]. However, it is present only at low concentrations in the mossy fiber terminals
(about 80 nM) [29]. The most abundant zinc-binding site is the GLAST glial glutamate transporter, which is responsible for glutamate removal from the synaptic cleft
into the glial cells [30, 31]. Zinc also forms complexes with 2-amino-3-(3-hydroxy5-methyl-isoxazol-4-yl), propanoic acid (AMPA) and kainic acid (KA) glutamate
receptors [29, 32–34], and potassium-ATP (K ATP ) channels [35, 36], with another
type of glutamate transporter, the EAAT4 [37–39], and with the L- and N-types of
voltage-dependent calcium channels (VDCCs) [40–42]. The concentration, affinity,
and kinetics of zinc-binding sites are included in the model and have a very large
impact on the behavior of zinc changes. On the other hand, the zinc uptake process
is largely unknown, being probably mediated by zinc transporters and/or by zinc
movements evoked by the electrochemical gradient [43–46]. In this model it was
assumed that uptake is much slower than release, and a time constant was chosen
for the latter process that is much larger than the time constant for the former (see
Section 2). With respect to zinc entry into postsynaptic neurons, which may include
NMDA receptors, voltage-dependent calcium channels, calcium-permeable AMPA/
kainate channels, and the Na/Ca exchanger [17, 18, 32, 34, 47], it is considered that
even the strongest stimulation protocol considered in this study is not strong enough
to open the postsynaptic zinc permeant routes. In the present model, three different
stimulation protocols were considered, named single (zinc release associated with a
single stimulus), short, and long (multiple release processes that last for more
times). It was considered that those stimulation processes evoked maximum cleft
free zinc concentrations of 10 nM, 100 nM, and 1 μM, respectively. These concentrations are close to the values suggested in previous studies performed with similar
types of stimulation [11, 19, 21, 27, 48]. Thus, in the present model, only cleft zinc
concentrations below or equal to 1 μM were considered; therefore, no zinc enters the
postsynaptic region, which may only occur for higher cleft zinc values [18, 20, 45].
The mossy fiber synapses have a very narrow synaptic cleft, measuring less than
20 nm [49–51]. For that reason, the movement of released glutamate and zinc, with
similar free diffusion coefficients, is very rapid, reaching the opposite side of the
cleft in a few microseconds. In hippocampal neurons, following an instantaneous
release from a vesicle, the decay of glutamate concentration is very fast (tens of
microseconds), being reduced to an almost constant value in about 50 μs [16].
Despite the more complex geometry of the mossy fibers [52], it can be assumed that
the zinc concentration has a similar time course. For this reason, the diffusion was
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Advances in Neural Signal Processing
sites in the synaptic cleft between a mossy fiber terminal and a pyramidal cell of the
hippocampal CA3 area, as previously reported [12]. Assuming that zinc is co-released
with the neurotransmitter glutamate, this model was constructed taking into account
previous studies that include computer simulations of glutamate dynamics in the
synaptic cleft [13–16]. In the zinc model [12], the variation of total cleft zinc changes
is obtained by subtracting two alpha functions, describing zinc release and zinc
uptake. These functions, characterized by rapid climb phases and slower decays, were
determined based on the assumed maximum amplitude and rising time values of cleft
free zinc concentration. The corresponding parameters were defined taking into
account experimental results, from optical and electrophysiological zinc experiments,
reporting cleft zinc changes [17–27].
The process of zinc clearance from the synaptic cleft may include various
actions, such as zinc binding, uptake, and entry into postsynaptic cells. Zinc can
bind to a variety of pre- and/or postsynaptic receptors, voltage-dependent ionic
channels, glutamate transporters expressed in glial cells, and also free molecules in
the cleft medium. One of the most important targets for zinc action is the Nmethyl-D-aspartate (NMDA) receptor-binding site with a high affinity for zinc
[28]. However, it is present only at low concentrations in the mossy fiber terminals
(about 80 nM) [29]. The most abundant zinc-binding site is the GLAST glial glutamate transporter, which is responsible for glutamate removal from the synaptic cleft
into the glial cells [30, 31]. Zinc also forms complexes with 2-amino-3-(3-hydroxy5-methyl-isoxazol-4-yl), propanoic acid (AMPA) and kainic acid (KA) glutamate
receptors [29, 32–34], and potassium-ATP (K ATP ) channels [35, 36], with another
type of glutamate transporter, the EAAT4 [37–39], and with the L- and N-types of
voltage-dependent calcium channels (VDCCs) [40–42]. The concentration, affinity,
and kinetics of zinc-binding sites are included in the model and have a very large
impact on the behavior of zinc changes. On the other hand, the zinc uptake process
is largely unknown, being probably mediated by zinc transporters and/or by zinc
movements evoked by the electrochemical gradient [43–46]. In this model it was
assumed that uptake is much slower than release, and a time constant was chosen
for the latter process that is much larger than the time constant for the former (see
Section 2). With respect to zinc entry into postsynaptic neurons, which may include
NMDA receptors, voltage-dependent calcium channels, calcium-permeable AMPA/
kainate channels, and the Na/Ca exchanger [17, 18, 32, 34, 47], it is considered that
even the strongest stimulation protocol considered in this study is not strong enough
to open the postsynaptic zinc permeant routes. In the present model, three different
stimulation protocols were considered, named single (zinc release associated with a
single stimulus), short, and long (multiple release processes that last for more
times). It was considered that those stimulation processes evoked maximum cleft
free zinc concentrations of 10 nM, 100 nM, and 1 μM, respectively. These concentrations are close to the values suggested in previous studies performed with similar
types of stimulation [11, 19, 21, 27, 48]. Thus, in the present model, only cleft zinc
concentrations below or equal to 1 μM were considered; therefore, no zinc enters the
postsynaptic region, which may only occur for higher cleft zinc values [18, 20, 45].
The mossy fiber synapses have a very narrow synaptic cleft, measuring less than
20 nm [49–51]. For that reason, the movement of released glutamate and zinc, with
similar free diffusion coefficients, is very rapid, reaching the opposite side of the
cleft in a few microseconds. In hippocampal neurons, following an instantaneous
release from a vesicle, the decay of glutamate concentration is very fast (tens of
microseconds), being reduced to an almost constant value in about 50 μs [16].
Despite the more complex geometry of the mossy fibers [52], it can be assumed that
the zinc concentration has a similar time course. For this reason, the diffusion was
112
Advances in Neural Signal Processing