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Coincidence detection and cortical rhythmicity are both greatly influenced by neurons' propensity to fire bursts of action potentials. In the neocortex, repetitive burst firing can also initiate abnormal neocortical rhythmicity (including epilepsy). Bursts are generated by inward currents that underlie a fast afterdepolarization (fADP) but less is known about outward currents that regulate bursting. We tested whether Kv2 channels regulate the fADP and burst firing in labeled layer 5 PNs from motor cortex of the Thy1-h mouse. Kv2 block with guangxitoxin-1E (GTx) converted single spike responses evoked by dendritic stimulation into multispike bursts riding on an enhanced fADP. Immunohistochemistry revealed that Thy1-h PNs expressed Kv2.1 (not Kv2.2) channels perisomatically (not in the dendrites). In somatic macropatches, GTx-sensitive current was the largest component of outward current with biophysical properties well-suited for regulating bursting. GTx drove ~40% of Thy1 PNs stimulated with noisy somatic current steps to repetitive burst firing and shifted the maximal frequency-dependent gain. A network model showed that reduction of Kv2-like conductance in a small subset of neurons resulted in repetitive bursting and entrainment of the circuit to seizure-like rhythmic activity. Kv2 channels play a dominant role in regulating onset bursts and preventing repetitive bursting in Thy1 PNs., (Published by Oxford University Press 2021.)

gamma-Aminobutyric acid (GABA) has been identified in axon terminals innervating neurons of the supraoptic nucleus and has been shown to inhibit the electrical activity of supraoptic neurons when applied iontophoretically. This study examines the effects of GABA and GABA antagonists on vasopressin (VP) release from organ-cultured explants of the hypothalamo-neurohypophyseal system (HNS). The GABA antagonists bicuculline and picrotoxin stimulated VP release in a concentration-dependent manner. These observations suggest that VP release by HNS explants is tonically inhibited by GABA. Exposure of HNS explants to GABA (10(-8)-10(-3) M) did not consistently alter basal VP release. This was true even when penicillin, which can block GABA-activated chloride channels, was omitted from the medium. Similarly, nipecotic acid, an agent that potentiates GABA activity by inhibiting GABA uptake, did not alter basal VP release; stimulation of VP release by acetylcholine and increases in osmolality was not diminished by the addition of 10(-5) M GABA. The failure of exogenous GABA to modify basal and stimulated VP release suggests that GABAergic inhibition of VP release is maximally activated by endogenously released GABA in cultured HNS explants. This is consistent with evidence for a local source of GABA in the supraoptic nucleus and suggests that one role of GABA in the regulation of VP release is that of a potent local inhibitory neurotransmitter.

Evidence is presented indicating that norepinephrine (NE) inhibits vasopressin (VP) release from the rat hypothalamo-neurohypophyseal explant under some, but not all, conditions in vitro. NE at 10(-5) M inhibited basal VP release and inhibited acetylcholine-induced release in a concentration-dependent fashion. However, the induction of VP release caused by the addition of NaCl (sufficient to yield a 10 mosmol/kg H2O increase in culture medium osmolality) was not reduced by NE in concentrations as high as 10(-5) M. An alpha-adrenergic receptor mediation of the inhibition of VP release by NE was suggested by the ability of phentolamine and phenoxybenzamine, but not propranolol, to block this effect. In addition, phentolamine at 10(-4) M, but not equimolar amounts of propranolol, increased VP release when added alone on day 2 of culture, but not on days 3 or 4. Histofluorescence examination of additional explants revealed that endogenous catecholamine was still present on day 2 within varicosities in the supraoptic nucleus, but diminished by days 3 and 4, suggesting that endogenous NE could influence basal VP release. The results indicate that NE can inhibit spontaneous and cholinergically stimulated VP release from the hypothalamo-neurohypophyseal explant, but osmotic stimulation renders the explants insensitive to attenuation of VP release by NE.