Retrograde Regulation of GABA Transmission by the Tonic Release of Oxytocin and Endocannabinoids Governs Postsynaptic Firing

Abstract

The probability of neurotransmitter release at the nerve terminal is an important determinant of synaptic efficacy. At some central synapses, the postsynaptic, or target, neuron determines neurotransmitter release probability (P r ) at the presynaptic terminal. The mechanisms responsible for this target-cell dependent control of P r have not been elucidated. Using whole-cell patch-clamp recordings from magnocellular neurosecretory cells in the paraventricular and supraoptic nuclei of the hypothalamus, we demonstrate that inhibitory, GABA synapses specifically onto oxytocin (OT)-producing neurosecretory cells exhibit a low P r that is relatively uniform at multiple synapses onto the same cell. This low P r results from a two-step process that requires the tonic release of OT from the postsynaptic cell. The ambient extracellular levels of neuropeptide are sufficient to activate postsynaptic OT receptors and trigger the Ca 2ϩ -dependent production of endocannabinoids, which act in a retrograde manner at presynaptic cannabinoid CB 1 receptors to decrease GABA release. The functional consequence of this tonic inhibition of GABA release is that all inhibitory inputs facilitate uniformly when activated at high rates of activity. This causes inhibition in the postsynaptic cell that is sufficiently powerful to disrupt firing. Blockade of CB 1 receptors increases P r at these synapses, resulting in a rapid depression of IPSCs at high rates of activity, thereby eliminating the ability of afferent inputs to inhibit postsynaptic firing. By playing a deterministic role in GABA release at the afferent nerve terminal, the postsynaptic OT neuron effectively filters synaptic signals and thereby modulates its own activity patterns.

Integration of Asynchronously Released Quanta Prolongs the Postsynaptic Spike Window

“…Likewise, vasopressin (VP) cells can release VP (Pow and Morris, 1989) or dynorphin (Watson et al, 1982). These molecules have all been shown previously to modulate neurotransmission in the PVN or supraoptic nucleus (Brussaard et al, 1996;Kombian et al, 1997;Hirasawa et al, 2003;Oliet et al, 2007). Although the vast majority of EPSCs recorded in MNCs displayed synchronous followed by asynchronous release, we did record EPSCs in some cells that displayed robust asynchronous release with little synchronous component.…”

“…Asynchronous release is not dependent on postsynaptic cell phenotype Oxytocin (OT) MNCs can release OT (Moos et al, 1989;Brussaard et al, 1996;Kombian et al, 1997;Ludwig et al, 2002;Sabatier et al, 2003) and endocannabinoids (Hirasawa et al, 2004;Oliet et al, 2007) from their dendrites. Likewise, vasopressin (VP) cells can release VP (Pow and Morris, 1989) or dynorphin (Watson et al, 1982).…”

“…These cases accounted for Ͻ10% of the total number of evoked responses recorded. Because transmitter release at inhibitory GABA synapses on MNCs can be regulated by the postsynaptic neuron (Oliet et al, 2007), we conducted experiments to determine whether the differences in release at glutamate synapses may also be a function of the target neuron. Here, we used a transgenic rat model in which eGFP is expressed exclusively by neurons producing VP (Ueta et al, 2005) to positively identify cells before recording (Fig.…”

Serotonin Evokes Endocannabinoid Release and Retrogradely Suppresses Excitatory Synapses

“…5-HT 2 Rs are known to couple to G q/11 -type G-proteins (Barnes and Sharp, 1999;Hoyer et al, 2002;Leysen, 2004;Parrish and Nichols, 2006), and activation of some other types of G q/11 -coupled receptors, such as metabotropic glutamate mGluR1/5 and muscarinic acetylcholine receptors, can promote endocannabinoid release from the dendrites of cells (Maejima et al, 2001;Varma et al, 2001;Kim et al, 2002;Chevaleyre et al, 2006;Oliet et al, 2007). Endocannabinoids can cross the synaptic cleft and bind to presynaptic cannabinoid-type 1 receptors (CB 1 Rs), which reduce the probability of transmitter release (Chevaleyre et al, 2006).…”

Novel Aspects of Glucocorticoids Actions on Energy Homeostasis and Hydromineral Balance

“…Several studies suggest that the endocannabinoid system can mediate not only the central effects of glucocorticoids but also independently modulate the excitability of postsynaptic terminals after the dendritic-mediated release of neuropeptides like OT (Hirasawa et al, 2004;McDonald et al, 2008;Oliet et al, 2007). This mechanism is likely to be implicated in the intra-hypothalamic feedback on hormone release and neuroplasticity (de Kock et al, 2003).…”