Random response fluctuations lead to spurious paired-pulse facilitation

Area of Science:

• Neuroscience
• Synaptic transmission
• Cellular electrophysiology

Background:

• Paired-pulse depression (PPD) is a common phenomenon in inhibitory synapses.
• The use-dependent model explains PPD by changes in neurotransmitter release probability.
• The applicability of this model to inhibitory synapses remains debated.

Purpose of the Study:

• Investigate the factors influencing paired-pulse ratio (PPR) in GABAergic inhibitory postsynaptic currents (IPSCs).
• Determine if the use-dependent model accurately describes PPD in CA1 pyramidal cells.
• Clarify the role of random fluctuations in PPR measurements.

Main Methods:

• Whole-cell voltage clamp recordings in CA1 pyramidal cells.
• Studied GABAergic IPSCs under conditions of reduced transmitter release (Cd2+, baclofen, altered stimulus intensity).
• Analyzed paired-pulse responses and their variability.

Main Results:

• PPR was sensitive to extracellular stimulus intensity across all conditions.
• Changes in PPR were not correlated with the amplitude of the first IPSC.
• PPR was correlated with the variability of individual trace responses.
• Spurious paired-pulse facilitation (PPF) can arise from averaging fluctuating PPRs, masking intrinsic synaptic properties.

Conclusions:

• Random fluctuations in synaptic response size significantly impact PPR.
• The use-dependent model is insufficient to explain PPD in this context.
• A revised method for calculating PPR (mean of second response/mean of first) avoids spurious PPF.
• A simple model suggests spurious PPF depends on the number of release sites and release probability.