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neighboring glutamatergic synapses (spaced by ~500 nm) and suggested that, due
to its high-affinity and perisynaptic location, NMDA receptor is an optimal candi-
date to mediate synaptic responses induced by glutamate spillover. In line with this,
at excitatory synapses in CA1 pyramidal neurons, Asztely et al. (
1997
) demon-
strated that spillover can activate NMDA but not AMPA receptors, while at
dendrodendritic synapses in the olfactory bulb, spillover activation of NMDA
receptors contributes in synchronizing the activity of olfactory principal cells
(Isaacson
1999
). Scimemi et al. (
2004
), in the hippocampus, isolated specific
molecular players for NMDA receptor-mediated synaptic cross talk by demon-
strating that 30-35 % of NMDA receptors are activated by glutamate spillover and
that only NR2B receptors were activated by spillover, while NR2A receptors
mediated conventional synaptic transmission. More recently, it has been also
shown in the layer 5 of the mouse prefrontal cortex that glutamate spillover
mediates the initiation of NMDA dendritic spikes with important implications for
the dendritic signal processing and computation (Chalifoux and Carter
2011
).
Besides the synaptic cross talk mediated by high-affinity receptors, glutamate
released from neighboring synapses has been shown to contribute to the activation
of low-affinity AMPAR during a single excitatory postsynaptic current (EPSC).
This phenomenon has been mainly described in the cerebellum at synapses formed
by mossy fibers and granule cells. These synapses, in which an individual mossy
fiber terminal innervates several granule cells, are encapsulated in a glomerular
structure that limits the neurotransmitter diffusion, thus favoring synaptic cross
talk. DiGregorio et al. (
2002
), indeed, demonstrated that excitatory postsynaptic
currents (EPSCs) recorded at granule cells are evoked both by conventional point-
to-point AMPA receptor activation and by glutamate spillover to AMPA receptor
belonging to neighboring synapses. In the same study, it has been shown that
glutamate spillover evokes both “pure spillover EPSCs” (characterized by slow
rise and decay kinetics) and contributes to slow down the decaying phase of
conventional EPSCs, accounting for the ~70 % of the total charge transfer at
granule cells. These results were corroborated by modeling studies that simulated
the glutamate diffusion within the cerebellar glomerulus (Nielsen et al.
2004
). Such
synaptic cross talk has been shown to reduce the trial-to-trial fluctuations and to
increase the efficacy of synaptic transmission. In addition, a more recent study
focusing on NMDA receptors at the glomerulus indicates that glutamate spillover
activates the high-affinity NMDA receptors equally to direct glutamate release,
corroborating the idea of increased synaptic reliability by synaptic cross talk
(Mitchell and Lee
2011
). Besides the glomerular glutamate diffusion, following
tetanic stimulation of cerebellar parallel fibers, glutamate spillover activates AMPA
receptors at glutamatergic synapses of stellate interneurons in the cerebellar mole-
cular layer, exerting an efficient frequency-dependent modulation of cerebellar
microcircuits (Carter and Regehr
2000
). Overall, the non-conventional activation
of synaptic receptors by neurotransmitter spillover contributes to refine synaptic
transmission by increasing its versatility, thus expanding the computational prop-
erties of neuronal circuits.
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