Impact of Synaptic Neurotransmitter Concentration Time Course on the Kinetics and Pharmacological Modulation of Inhibitory Synaptic Currents

Abstract

The time course of synaptic currents is a crucial determinant of rapid signaling between neurons. Traditionally, the mechanisms underlying the shape of synaptic signals are classified as pre- and post-synaptic. Over the last two decades, an extensive body of evidence indicated that synaptic signals are critically shaped by the neurotransmitter time course which encompasses several phenomena including pre- and post-synaptic ones. The agonist transient depends on neurotransmitter release mechanisms, diffusion within the synaptic cleft, spill-over to the extra-synaptic space, uptake, and binding to post-synaptic receptors. Most estimates indicate that the neurotransmitter transient is very brief, lasting between one hundred up to several hundreds of microseconds, implying that post-synaptic activation is characterized by a high degree of non-equilibrium. Moreover, pharmacological studies provide evidence that the kinetics of agonist transient plays a crucial role in setting the susceptibility of synaptic currents to modulation by a variety of compounds of physiological or clinical relevance. More recently, the role of the neurotransmitter time course has been emphasized by studies carried out on brain slice models that revealed a striking, cell-dependent variability of synaptic agonist waveforms ranging from rapid pulses to slow volume transmission. In the present paper we review the advances on studies addressing the impact of synaptic neurotransmitter transient on kinetics and pharmacological modulation of synaptic currents at inhibitory synapses.

Impairment of GABA transporter GAT-1 terminates cortical recurrent network activity via enhanced phasic inhibition

“…Under conditions of massive release, the most plausible consequences of mildly impeding GABA uptake by GAT-1 are longer GABA pulses in the synaptic cleft, and enhanced spillover of GABA out of the synaptic cleft. Longer GABA pulses in the synaptic cleft likely recruit additional synaptic GABA A receptors, a proportion of which is not activated or saturated under normal conditions (Hajos et al, 2000; Gonzalez-Burgos et al, 2009; Barberis et al, 2011; Petrini et al, 2011). Enhanced spillover should in addition accentuate the impact of peri- and extrasynaptic receptors as well as of unoccupied synaptic receptors at inactive release sites (Barbour, 2001; Overstreet and Westbrook, 2003).…”

Enhanced GABAA-Mediated Tonic Inhibition in Auditory Thalamus of Rats with Behavioral Evidence of Tinnitus

“…GABAergic inputs to MGB act via postsynaptic GABA A receptors (GABA A Rs) that are heterogeneous (Sur et al, 1999;Richardson et al, 2012). MGB synapses express low-affinity, fast-desensitizing GABA A Rs (␣ 1 , ␤ 2 , ␥ 2 subunits) that mediate fast synaptic transmission and enable high temporal precision (Mozrzymas, 2004(Mozrzymas, , 2010Farrant and Nusser, 2005;Barberis et al, 2011). In addition, MGB expresses high levels of GABA A Rs containing ␣ 4 -and ␦-subunits that mediate nondesensitizing tonic inhibition (Richardson et al, 2011).…”

Small-Volume Analysis of Cell–Cell Signaling Molecules in the Brain

“…Neuropeptide binding affinity to cloned receptors is nearly 1000 Â higher than that of classical transmitters, often acting far from the synaptic cleft. In contrast, classical transmitters can be found at high local concentrations in the synaptic cleft (Barberis et al, 2011), but have short half-lives in the brain's extracellular space (Merighi et al, 2011). These facts suggest that the temporal dynamics and concentration profiles are different among distinct classes of bioactive compounds.…”