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The mechanisms responsible for this target-cell dependent control of<jats:italic>P<\/jats:italic><jats:sub>r<\/jats:sub>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<jats:italic>P<\/jats:italic><jats:sub>r<\/jats:sub>that is relatively uniform at multiple synapses onto the same cell. This low<jats:italic>P<\/jats:italic><jats:sub>r<\/jats:sub>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<jats:sup>2+<\/jats:sup>-dependent production of endocannabinoids, which act in a retrograde manner at presynaptic cannabinoid CB<jats:sub>1<\/jats:sub>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<jats:sub>1<\/jats:sub>receptors increases<jats:italic>P<\/jats:italic><jats:sub>r<\/jats:sub>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.<\/jats:p>","DOI":"10.1523\/jneurosci.2676-06.2007","type":"journal-article","created":{"date-parts":[[2007,2,7]],"date-time":"2007-02-07T23:15:04Z","timestamp":1170890104000},"page":"1325-1333","source":"Crossref","is-referenced-by-count":100,"title":["Retrograde Regulation of GABA Transmission by the Tonic Release of Oxytocin and Endocannabinoids Governs Postsynaptic Firing"],"prefix":"10.1523","volume":"27","author":[{"given":"St\u00e9phane H. 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