The effects of geometrical parameters on synaptic transmission: a Monte Carlo simulation study

Abstract

Monte Carlo simulations of transmitter diffusion and its interactions with postsynaptic receptors have been used to study properties of quantal responses at central synapses. Fast synaptic responses characteristic of those recorded at glycinergic junctions on the teleost Mauthner cell (time to peak approximately 0.3-0.4 ms and decay time constant approximately 3-6 ms) served as the initial reference, and smaller contacts with fewer postsynaptic receptors were also modeled. Consistent with experimental findings, diffusion, simulated using a random walk algorithm and assuming a diffusion coefficient of 0.5-1.0 x 10(-5) cm2 s(-1), was sufficiently fast to account for transmitter removal from the synaptic cleft. Transmitter-receptor interactions were modeled as a two-step binding process, with the double-bound state having opened and closed conformations. Addition of a third binding step only slightly decreased response amplitude but significantly slowed both its rising and decay phases. The model allowed us to assess the sources of response variability and the likelihood of postsynaptic saturation as functions of multiple kinetic and spatial parameters. The method of nonstationary fluctuation analysis, typically used to estimate the number of functional channels at a synapse and single channel current, proved unreliable, presumably because the receptors in the postsynaptic matrix are not uniformly exposed to the same profile of transmitter concentration. Thus, the time course of the probability of channel opening most likely varies among receptors. Finally, possible substrates for phenomena of synaptic plasticity, such as long-term potentiation, were explored, including the diameter of the contact zone, defined by the region of pre- and postsynaptic apposition, the number and distribution of the receptors, and the degree of vesicle filling. Surprisingly, response amplitude is quite sensitive to the size of the receptor-free annulus surrounding the receptor cluster, such that expansion of the contact zone could produce an appreciable increase in quantal size, normally attributed to either the presence of more receptors or the release of more transmitter molecules.

Number and Density of AMPA Receptors in Single Synapses in Immature Cerebellum

“…Moreover, 2pEPSCs obtained from single synapses had low variability in 62% decay time (CV, 0.15), suggesting low variability of the clearance (Nusser et al, 2001). Actually, the reliability of NSFA was further improved by a slower diffusion constant of glutamate as confirmed by our simulation (data not shown), probably because of the increment of saturation level (Kruk et al, 1997).…”

Developmental Changes of GABA Synaptic Transient in Cerebellar Granule Cells

“…Differences in these parameters in young and old neurons could be potentially responsible for the observed differential age-dependent inhibition by fast-off antagonists. However, although several studies have shown (at both excitatory and inhibitory synapses) that the neurotransmitter concentration peak and temporal profile critically depend on these parameters (Kleinle et al, 1996;Kruk et al, 1997;Barbour, 2001), much less is known about their developmental changes. When interpreting the data obtained from a simple model of cultured neurons, it is important to consider to what extent the developmental paradigm observed in vitro could reproduce that observed in vivo.…”

Evidence for Ectopic Neurotransmission at a Neuronal Synapse

“…5B). Our finding that α7-nAChRs buffer the availability of ACh for binding to α3*-nAChRs suggests a role for spatial organization in determining intrinsic synaptic variability (18,23,25,30,38). A similar, cleft-limited diffusion buffering has been observed at snail synapses in culture where the extracellular glial-derived ACh binding protein modulates synaptic transmission by competing for released ACh (39,40).…”

“…The source of mEPSC distribution variability has been attributed variously to the size of synaptic vesicles and the concentration of agonist in the cleft (25,30,36), the density of postsynaptic receptors (37), the release-site location or local environment (36), and the stochastics of receptor flickering (18). Our model CG is most sensitive to the number of ACh molecules released into the cleft, implicating vesicle size as the primary source of variability (see normalized derivative sensitivity above; Fig.…”