Differences in Synaptic GABAA Receptor Number Underlie Variation in GABA Mini Amplitude

Abstract

In many neurons, responses to individual quanta of transmitter exhibit large variations in amplitude. The origin of this variability, although central to our understanding of synaptic transmission and plasticity, remains controversial. To examine the relationship between quantal amplitude and postsynaptic receptor number, we adopted a novel approach, combining patch-clamp recording of synaptic currents with quantitative immunogold localization of synaptic receptors. Here, we report that in cerebellar stellate cells, where variability in GABA miniature synaptic currents is particularly marked, the distribution of quantal amplitudes parallels that of synaptic GABA(A) receptor number. We also show that postsynaptic GABA(A) receptor density is uniform, allowing synaptic area to be used as a measure of relative receptor content. Flurazepam, which increases GABA(A) receptor affinity, prolongs the decay of all miniature currents but selectively increases the amplitude of large events. From this differential effect, we show that a quantum of GABA saturates postsynaptic receptors when <80 receptors are present but results in incomplete occupancy at larger synapses.

Activity-dependent scaling of GABAergic synapse strength is regulated by brain-derived neurotrophic factor

“…This suggests that activity blockade may induce a coordinated set of presynaptic and postsynaptic changes at inhibitory synapses. In support, previous evidence demonstrated that variations in both the GABA content of vesicles (Frerking et al, 1995) and the number of postsynaptic GABA A receptors (Nusser et al, 1997(Nusser et al, , 1998 determine mIPSC amplitude. Moreover, a reduction in both the staining intensity of GAD-65 and synaptic GABA A receptors was previously observed in cultured cortical neurons after activity blockade (Kilman et al, 2002).…”

Impact of single-site axonal GABAergic synaptic events on cerebellar interneuron activity

“…It has been shown previously that there is a positive correlation between the size of the active zone and that of the postsynaptic density (Schikorski and Stevens, 1997;Harris and Stevens, 1988); likewise, the size of the postsynaptic density determines the quantal size: a larger postsynaptic area allows a higher number of receptors (Auger and Marty, 1997;Nusser et al, 1997). Moreover, our recent evidence suggests that the size of the active zone is positively correlated with the RRP in presynaptic specializations Pulido et al, 2015).…”

“…To functionally test the spatial resolution, we performed a series of experiments in which the laser was sequentially Laser-evoked ASCs are heterogeneous across release sites (Auger and Marty, 1997;Nusser et al, 1997). The amplitudes in individual varicosities could be described by a Gaussian distribution, and the average coefficient of variation estimated from individual sites was significantly smaller than the coefficient of variation calculated from the amplitudes corresponding to all the stimulated varicosities (CV ind : 0.16 ± 0.02; n = 41 varicosities; CV all = 0.55; n = 64 pointed to the center of a varicosity and to nearby positions.…”

Molecular and synaptic organization of GABAA receptors in the cerebellum: Effects of targeted subunit gene deletions

“…In addition, PC also carry extrasynaptic GABA A receptors diffusely distributed on the cell surface and are modulated by tonic inhibition, notably due to GABA release from basket cells (25). Similar, high frequency and high amplitude sIPSCs have been well characterized also in stellate cells (26,27), underscoring the major role played by postsynaptic GABA A receptors in the molecular layer.…”