Independent Sources of Quantal Variability at Single Glutamatergic Synapses

“The latter is consistent with electron microscopy studies (Nusser et al., 1998; Takumi et al., 1999) and the observation that bigger synapses produce bigger responses (Andrasfalvy and Magee, 2001; Matsuzaki et al., 2001).”

“R(2) xiP ljðx; tÞdx ði; j 1⁄4 1; 2; l 1⁄4 o; cÞ (41)”

“…of some of these parameters using either the Monte Carlo method (Bartol et al. 1991; Faber et al. 1992; Stiles et al. 1996; Kruk et al. 1997; Glavinovic and Rabie 1998; Franks et al. 2002, 2003; Raghavachari and Lisman 2004) or other models (Kleinle et al. 1996; Ventriglia and Di Maio 2002, 2003).”

“Computational simulations have therefore been instrumental to unravel the functional aspects of synaptic nano-architecture (Franks et al., 2003; Raghavachari and Lisman, 2004; Savtchenko and Rusakov, 2014; Xie et al., 1997).”

“…may have different competing causes in practice, ranging from short–length stochasticities, e.g., those associated with the opening and closing of the vesicles and with local variations in the neurotransmitters concentration, to time lags in the incoming long–length signals (Franks et al., 2003).”

“Previous Monte Carlo models have dealt successfully with a comparable extent of neuropil surrounding one synapse (21,26–28), including extracellular diffusion in a complex geometrical environment (29,30).”

“It is well-known, for instance, that synapses exhibit a high variability with a diverse origin during information transmission, such as stochastic release of neurotransmitters, variations in chemical concentration through synapses and spatial heterogeneity of synaptic response over dendrite tree [16].”

“vesicles can represent an important source of variation in postsynaptic responses of AMPARs [29,65,66].”

“…the properties of neuromuscular synapses (del Castillo and Katz, 1954) the greater variation in mini amplitudes at central synapses (Hanse and Gustafsson, 2001; Franks et al., 2003; Hardingham et al., 2010) necessitated different techniques to recover robust results in the central nervous system.”

“What remains to be seen is whether synaptic CAMs play a role in aligning the presynaptic release sites on the active zone relative to the receptor clusters on the PSD surface, whose degree of registration is expected to significantly affect the extent of postsynaptic receptor activation [65].”

“5 [38] and that 20% of the synaptic AMPA receptors are fully occupied [44]).”

“Modeling studies [22 ,53] suggest that high concentrations of transmitter are short-lived and restricted to locations very near the site of release.”

“During LTP, PSDs on spines with polyribosomes undergo some enlargement that is greater than on spines without SER, but less than on spines with SER (figure 7 h ) [54,106].”

“Contrary to previous works (6, 11, 14, 15), our analysis does not use the description of channels involving a time dependent multi-”

“This approach avoids complicating factors such as presynaptic adaptions (Zucker & Regehr, 2002; Cho & Askwith, 2008), the geometry of and clearance from the synaptic cleft (Clements et al. 1992; Franks et al. 2003; Graydon et al. 2014) or metabotropic/cell signalling influences (Gao et al.”

“32,34 A Monte Carlo approach can also be used 100 ; in this case, a simulator such as MCell should be considered (http://www. mcell.cnl.salk.edu/).”

“The Journal of Comparative Neurology | Research in Systems Neuroscience 522:4023–4042 (2014) 4023 Matsuzaki et al., 2001; Franks et al., 2003; Ganeshina et al., 2004; Tarusawa et al., 2009).”

“…and release mechanisms (Choi 1988; Greenamyre et al. 1988; Coyle and Puttfarcken 1993; Moghaddam and Adams 1998; Araque et al. 1999, 2014; Tapia et al. 1999; Marino et al. 2001; Franks et al. 2003; Haydon and Carmignoto 2006; Javitt et al. 2011; Santello et al. 2012; Perez-Alvarez et al. 2014).”

“For example, the alignment of receptors with the presynaptic release site is an important factor that influences the postsynaptic response [39, 66, 67].”

“…synapses show a high variability with a diverse origin, such as the stochastic release and transmission of neurotransmitter vesicles, variations in the Glutamate concentration through synapses and the spatial heterogeneity of the synaptic response in the dendrite tree (Franks et al., 2003).”

“When release is monitored via the postsynapse, the static, electrotonic structure of the cell and its active conductances can limit the temporal readout and contaminate the single events, respectively (Bekkers and Stevens, 1996; Franks et al., 2003).”

“between 50%and 90%,which is in the range found at single synapses in the brain.(38,39) There was no discernible shift in the distribution of CLN synaptic responses in iSPNs following 6-OHDA lesioning (Fig.”

“The kinetics of the transporters involved binding, internalizing, and unbinding glutamate molecules and was modeled by a Markov scheme.(1) In the model for the ketogenic diet, the vesicle load was reduced to 2,000 molecules.”

“Concomitantly to the development of these new microscopy techniques, the application of improved electron microscopy (freeze-fracture replica, pre-embedding) and synaptic modeling alluded to a potential sub-compartmentalization of the synapse [39,40].”

“As previously reported [16, 17] simulation results indicated that NMDAR-mediated EPSP amplitudes were not location-dependent (Fig 7B); these results reflect the relatively high affinity of glutamate for NMDAR, which essentially eliminates the influence of location on receptor occupancy.”

“Meanwhile, significant variability is recognized within neuronal and synaptic populations [1–11]; its relevance remains unclear [10, 11].”

“These noise additions could arise here, as it does in many other circuits [62,63], through variations in vesicle release probability or in the number of neurotrans-mitters or synaptic vesicles [27,64,65].”

“In this particular case trial-to-trial variations of neurotransmitter concentration in the synaptic cleft [46,60], and other presynaptic factors [45,60–62] should not contribute to the fluctuations.”

“…to a sufficiently high concentration of glutamate to become activated, ultimately it is the local density of receptors apposing the release site that determines the strength of a synaptic response (Franks et al., 2003; Raghavachari and Lisman, 2004; Lisman et al., 2007; Freche et al., 2011).”

“The exact reason for this is as yet unknown, though models suggest that synaptic strength can vary strongly depending on the correlation of post-synaptic receptor placement and presynaptic glutamate release [14,47].”

“Among the major sources of variability in quantum response, the following should be emphasized: (1) inconstant number of neurotransmitter molecules per single quantum due to different size of vesicles and/or different concentration of neurotransmitter in them; (2) random process of diffusion of a relatively small numb…”

“Some claim that high concentrations of transmitter are confined to a small domain within the postsynaptic density (PSD) area (Franks et al., 2003), and some show strong evidence that glutamate can spill over from the synaptic cleft to activate low-affinity receptors located on nearby synapses…”

“This is consistent with actual features of natural systems such as, for example, variations of the glutamate concentration in the synaptic cleft, and differences in the potency released from different locations on the active zone of the synapses [Franks et al.(2003)].”

“Biologically, the probability of neural synapse excitation and receptor binding depends on available neurotransmitter concentration [51].”

“In the simulations, Franks et al. (2003) assumed that 2,000 molecules were released through a fusion pore.”

“45,63 Therefore, if there were changes in transsynaptic alignment, changes in EPSC or mEPSC kinetics would be apparent.”

“…contain scaffolding proteins to anchor glutamate receptors for regular synaptic transmission, AMPARs are known to exist in extrasynaptic membrane near the PSD (Nair et al., 2013; Tao-Cheng et al., 2011) and likely be able to support synaptic transmission (Franks et al., 2003; Tardin et al., 2003).”

“The stochastic conformational fluctuations that generate the variance in the number of open ion channels (‘‘noise,’’ which here refers only to the noise due to channel opening/closing) can have a substantial effect on the membrane potential of excitable cells [5–9].”

“The reliability of neurotransmitter release can be highly variable: since the 1950’s, experimental data from electrophysiological, molecular, and imaging studies have demonstrated that synaptic terminals can individually set their neurotransmitter release probability dynamically through local feedback regulation [9],…”

“…Lisman, 2004), vesicle size (Bekkers et al., 1990; Karunanithi et al., 2002; Guo et al., 2015), cleft transmitter concentration (Liu et al., 1999; Franks et al., 2003), fusion pore kinetics (Guo et al., 2015), and release site-receptor registration (Uteshev and Pennefather, 1996; MacGillavry et…”

“What is clear is that the brain exhibits stochasticity at the synaptic scale, with synaptic vesicle release being best described as stochastic for many decades [9].”

“For example, variations of the glutamate concentration in the cleft and differences in the potency of vesicles released from different locations on the active zone are shown to be the two main contributors to the quantal variability at single glutamatergic synapse [25].”

“…neurotransmitter vesicles, variation in the postsynaptic response along the dendritic tree, which in turn has several sources (e.g., variations of the glutamate concentration in the synaptic cleft) and differences in the power released from different locations on the active zone of the synapses [5].”

“…or amplitude of MEPSCs, respectively; Kirov et al. 1999; Murthy et al. 2001; Burrone and Murthy 2003), but these traditional criteria no longer provide unequivocal support for assumed presynaptic or postsynaptic sites (e.g. see Karunanithi et al. 2002; Franks et al. 2003; Rich and Wenner 2007).”

“These factors may lead to substantial variability in synaptic currents (Franks et al. 2003; Lisman et al. 2007; Faisal et al. 2008) and it will be important to establish their influence relative to that of stochastic ion channel gating.”

“This view was mainly based on studies dealing with IAMPA variability (see for instance Franks et al., 2002; 2003).”

“Synaptic transmission in the excitatory synapse in the hippocampus was simulated using a Monte-Carlo method (Wahl et al. 1996; Franks et al. 2003; Ventriglia 2004).”

“For example, identifying different sources of variability can guide the search into potential mechanisms that shape neural responses (Softky and Koch, 1993; Franks et al., 2003; Goris et al., 2014).”

“…we note that the anatomy of synapses in the central nervous system is different from that of the NMJ, that is, there are many small synapses distributed in the whole dendrite while the number of receptors in a single synapse is relatively small Franks et al. (2003); Nimchinsky et al. (2004).”

“Moreover, computational simulations predict that changes in the shape of the PSD are a way to align postsynaptic receptors to presynaptic release sites (Franks et al., 2003; Savtchenko and Rusakov, 2014).”

“A reasonable level of noise for PNs would be in the range 0–50% (Bhandawat et al., 2007), and for synaptic transmission, would be in the range of 15-25% (Bekkers et al., 1990; Franks et al., 2003).”