Electrodiffusion of synaptic receptors: a mechanism to modify synaptic efficacy?

Abstract

We analysed physical forces that act on synaptic receptor-channels following the release of neurotransmitter. These forces are: 1) electrostatic interaction between receptors, 2) stochastic Brownian diffusion in the membrane, 3) transient electric field force generated by currents through open channels, 4) viscous drag force elicited by the flowing molecules and 5) strong in-membrane friction. By considering alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type receptors, we show that, depending on the size and electrophoretic charge of the extracellular receptor domain, release of an excitatory neurotransmitter (glutamate) can induce receptor clustering towards the release site on a fast time scale (8-100 ms). This clustering progresses whenever repetitive synaptic activation exceeds a critical frequency (20-100 s(-1), depending on the currents through individual channels). As a result, a higher proportion of the receptors is exposed to higher glutamate levels. This should increase by 50-100% the peak synaptic current induced by the same amount of released neurotransmitter. In order for this mechanism to contribute to long-term changes of synaptic efficacy, we consider the possibility that the in-membrane motility of the AMPA receptors is transiently increased during synaptic activity, e. g., through the breakage of receptor anchors in the postsynaptic membrane due to activation of N-methyl-d-aspartic acid receptors.

Effect of Voltage Drop within the Synaptic Cleft on the Current and Voltage Generated at a Single Synapse

“…Another important implementation follows from the inhomogeneity of the intracleft voltage, indicating a significant voltage gradient between inner parts and the edge of the synaptic contact. The gradients estimated from the contact dimensions and the voltages in our model (ϳ10 4 V/m) are sufficiently high to cause an electrophoretic drift of charged molecules within the cleft (Savtchenko et al, 1999). In the excitatory synaptic contacts, like those considered in this study, negatively charged molecules should be electrophoretically pushed out of the cleft and positively charged ones should be drawn into the cleft.…”

Characterization of the influence of Amyloid β (1-42) By Way of Modeling Synaptic Cleft with an RC Electronic Circuit

“…As can be seen from Figure 3 some of the spikes measured at the output of the later circuit are delayed or shifted compared to the ones measured at the output of the former circuit. This shift can also be linked to the assumption that Sialylation (Sialic acid) could cause a large depolarising shift in the activation curve [15] of voltage-gated sodium channels which consequently alter the spiking threshold of the neuron without any alteration in the patch-clamp recorded membrane voltage Vm in hippocampal pyramidal neurons [16].…”

“…Theoretical systematic models introduced for amyloid channel-like structures and Alphasynuclein based highly conductive ion channels [15] also do support these ion channellike structures. It has been shown that Sialylation (Sialic acid) can cause a large depolarising shift in the activation mechanism [16] of voltage-gated sodium channels and so altering the spiking threshold of the neuron without any variation in the patch-clamp recorded membrane voltage Vm in hippocampal pyramidal neurons [17]. Now, the issue is that could these small peptides, which can only partly infuse membrane, have the potential of formation of ionic amyloid channel models.…”