For intrasynaptic factors are meant mechanisms operating at the AZ level or the PSD domain. For the extrasynaptic, any effector that is in the synaptic “cylinder” or works outside of it is mentioned. The intrasynaptic factor can be divided into pre and post synaptic factors that affect EPSP variability.
Presynaptic dependent EPSP variability
The first point to be emphasized about the source of presynaptic variability is that the probability of a vesicle release after a presynaptic spike is not 1 and the range can be as wide as 0.2-0.91. The modification of the probability of release was associated with presynaptic (non-NMDA dependent) long-term potentiation (LTP), assuming that the synapse-dependent efficacy activity is due to the increased probability of release. This point is crucial to understanding how the presynaptic nerve code is synaptically encoded because it means that not all presynaptic spikes are encoded by an EPSP.
Also, if this probability changes as a function of activity, it means a different number of EPSP codes for a given number of presynaptic spikes based on previous activity. In terms of information, not all presynaptic lice are transferred, only some of them are transferred, and the size of the fraction depends on the activity. Moreover, the sequence of EPSPs is not linearly collected on the postsynaptic side. This does not mean that only some of the bits that make up the presynaptic “word” are transferred, but that their postsynaptic representation is highly variable and how many bits are transferred (changes with the efficiency as the probability of oscillation changes) and the timing between bits transmitted.
Although vesicular release is considered of quantitative type, single vesicle release may produce different responses due to several presynaptic factors. The position of the vesicle with respect to the central axis of the cylinder limited by AZ and PSD (eccentricity) is an important factor. For a particular configuration of PSD, release of glutamate from a more peripheral vesicle will produce an EPSC of smaller amplitude than that centered on the AZ-PSD central axis. Another important factor is the amount of molecules entering the vesicle. In fact, the vesicle concentration is highly variable, ranging from 60-210 mM. (with average -140 mM)
Assuming an average inner radius of 23 nm of the vesicle, it is clear that the number of glutamate molecules released for a single bit of information is highly variable. Variable number of molecules produce EPSC of different amplitude. In our first study on a single glutamatergic response, the combination of molecule number and release position is considered as stochastic factors. However, given the large variability of glutamate concentration in vesicles, one thousand possible combinations of “position-molecule number”, this could be a powerful system for presynaptic regulation of information transfer.
In this context, an interesting question arises: “What is the ‘mechanism’ that ‘decides’ the ‘position-number’ combination of ‘glutamate molecules’ on the right combination for a given presynaptic increase?” The SNARE complex may be a candidate for this decision role, due to its different configurations depending on membrane activity. Although a single vesicle opening of a single presynaptic spike in the majority of cases was less than 1, a multivicular release was observed in some cases. The polymorphic version found in some experiments raises many other interesting questions. The most relevant; What is the relationship with the number of vesicles opened for the sudden increase of the transferred information? Another interesting question is, what is the role of multi-particle oscillation if usually a single version does not provide postsynaptic saturation of the answer? To summarize, the most important presynaptic factor of EPSP variability are:
Probability of vesicle release after a single presynaptic spike and its dependence on past activity
• Possibility of multivicular release
Number of molecules in the vesicle released
Position of the vesicle released (eccentricity)
Ca 2+ different modulation of the SNARE complex
Postsynaptic Dependent EPSP Variability
PSD is the postsynaptic area that contains receptors (AMPA and NMDA) with different roles. The number of receptors between different synapses is highly variable, but also varies as a function of their maturity and activity at the same synapse. The number of AMPA receptors in a typical hippocampal synapse can range from 0 (with AMPA-silent synapses to 80-100. AMPA number is related to synaptic maturation and potentiation and is strongly associated with phenomena such as memory formation and learning (among others.
Some of these mechanisms can alter the properties of a synapse in less than a second if the presynaptic neuron gives an appropriate stimulus. The variability of the AMPA number produces not only amplification of a synapse but also a depotentation (by removing AMPA and both mechanisms are dependent on Ca 2+ and NMDA. AMPA can be added (or removed) due to migration from the extrasynaptic membrane space to PSD, or According to some authors, the number of NMDA receptors can also vary as a function of activity. This point is not trivial for understanding synaptic response variability. By changing the number of receptors it changes the total conductivity and the current that the synapse can produce for a single presynaptic spike.
Different synaptic responses obtained for a single vesicle release. Different amplitudes may be due to either presynaptic regulation (eg, different positions of the vesicle or different number of molecules) or postsynaptic regulation (eg, different number of receptors at the time of EPSP onset or different membrane voltage). Both AMPA and NMDA are tetramers (made up of four subunits) arranged as dimers of dimers. The dimeric and tetrameric composition produces a configuration mosaic, each with different electrophysiological properties from the others.
Their conductivity mediates on different dimeric compositions, indeed for AMPA 15 ± 10 pS and NMDA for 40 ± 15 pS. This means that the variability induced due to, for example, the splice activity of an AMPA, will provide a variation in response depending on the dimeric composition (conductivity) of the newly added receptor. The current generated by the opening of the receptors (EPSC) produces a variation of the membrane potential (EPSP) on the postsynaptic side, depending on the biophysical properties of the postsynaptic membrane. The glutamatergic synapse is located on top of a spine, which is considered by many authors to be a discrete electrical compartment with high input impedance. The general equation that produces EPSC is derived from Ohm’s law: