Biomedical Engineering Reference
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respectively, it may be argued that local calcium increase may concomitantly
induce LTP at glutamatergic synapses and LTD at GABAergic synapses leading
to a strong unbalance tipped toward excitation.
9.5.4 Future Perspectives
It has been shown that, as postulated by the Bienestock-Cooper-Munro (BCM)
rule, at glutamatergic synapses, high calcium increase would lead to LTP, while
moderate calcium entry would trigger LTD (Lisman
2001
). At GABAergic synap-
ses, conversely, sustained calcium entry leads to synaptic depression
(Lu et al.
2000
; Bannai et al.
2009
) while moderate calcium may lead to LTP
(Marsden et al.
2010
; Petrini personal communication). This opposite “calcium
rule” at glutamatergic and GABAergic synapses may determine a complex scenario
in which calcium spread from glutamatergic synapses may induce different plas-
ticity at neighboring GABAergic synapses according to the concentration reached
by calcium. In this context, due to intracellular calcium diffusion, the relative
distance of GABAergic synapses from glutamatergic synapses may play an impor-
tant role in setting the calcium concentration that induced LTD or LTP, linking the
distribution of glutamatergic and GABAergic synapses on the neuronal dendrites to
the activity-dependent tuning of synaptic strength and excitatory to inhibitory (E/I)
balance. As mentioned above, it has been shown that the amplitude of synaptic
current can be modulated by fast exchange between synaptic and extrasynaptic
receptors.
Very likely this concept can be further extended, assuming that by diffusing
between two or more synapses (transsynaptic diffusion), a receptor can bring to the
next synapse the “history” of its experience in the previous synapse, creating a cross
talk between synapses. For example, if a given synapse undergoes sustained
activity, the consequent accumulation of desensitized receptors could reduce the
short-term efficacy of adjacent synapses through lateral transsynaptic diffusion of
desensitized receptors. A requirement for such diffusion-mediated “information
exchange” between synapses is that specific receptor states (e.g., open or
desensitized) persist long enough to allow receptor diffusion between two or
more synapses. This condition is fulfilled by desensitized states of GABA
A
Rs
that can persist up to 1-10 s. According to measurements of diffusion coefficients
of GABA
A
R and glutamate in extrasynaptic compartments (0.2-1
m
2
/s), we
estimate that, during the desensitized state, those receptors can cover distances in
the range of 0.9-6.3
ʼ
ʼ
m, on par with the typical distance between adjacent synap-
ses, e.g., 1.5-2
m in hippocampal dendrites (Fig.
9.6b
). To explore our hypothesis,
we are currently exploiting light-gated glutamate receptors (LiGluK2), an
optogenetic tool developed in the Isacoff Lab, that can be effectively switched to
either the open/desensitized or closed state by illuminating with 380 nm or
>
ʼ
460 nm light, respectively. By activating LiGluK2 receptors at individual synap-
ses,
indeed,
it
is possible to explore the receptor diffusion in “controlled
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