1. In hippocampal CA1 neurons of rat brain slices, a Ca(2+)-dependent slow afterhyperpolarization (sAHP) and underlying K+ current (IsAHP) are activated by Ca2+ influx and presumably reflect the time course of the intracellular Ca2+ signal produced by neuronal stimulation. We tested the hypothesis that when exogenous Ca2+ chelators become the predominant mobile Ca2+ buffer in the neuron, they alter the shape of intracellular Ca2+ signals responsible for IsAHP. The nature of this alteration provides insight into the mechanism of IsAHP generation. 2. Derivatives of 1,2-bis-[2-amino phenoxy] ethane N,N,N',N' tetraacetic acid (BAPTA) with different dissociation constants (KDS) for Ca2+ ranging from 0.15 to 7,000 microM were used to test this hypothesis. We also examined the effects of ethylene glycolbis (beta-aminoethyl either)-N,N,N',N'-tetraacetic acid (EGTA), which has a KD similar to that of BAPTA for Ca2+, but which binds and releases Ca2+ 100 times more slowly. When delivered to the cytoplasm by dialysis from a patch pipette, these chelators potentiated, inhibited, or had no effect on IsAHP depending on their concentration, affinity, and binding kinetics. 3. IsAHP decayed exponentially over much of its time course, with a half-decay time of 0.9 +/- 0.1 s (mean +/- SE, n = 22). Immediately after breakthrough into the whole cell configuration, there was an initial period of approximately 5 min during which IsAHP magnitude increased approximately 3.5-fold with no change in time course. Thereafter, the time course and amplitude of IsAHP were stable for > 45 min. 4. Addition of 1 mM of the high-affinity chelators 5,5'-dimethyl BAPTA or BAPTA to the pipette solution first increased the decay time of IsAHP 1.5-fold. However, within 10-15 min after break-through, the current was abolished. Addition of Ca2+ (0.1-1.0 mM) to the patch pipette containing the BAPTA derivatives reduced the ability of a given concentration of high-affinity chelator to inhibit IsAHP and also prolonged the period of IsAHP enhancement. A similar prolongation of the period of enhancement with even less attenuation of IsAHP was apparent with 0.1 mM 5,5'-dimethyl BAPTA and 0.1 mM Ca2+. 5. The intermediate-affinity chelator 4.4'-difluoro BAPTA (1 mM) prolonged the decay phase of the sAHP/IsAHP without attenuating the current. A twofold prolongation of IsAHP also was observed in neurons dialyzed with internal solution containing 3 mM EGTA and 0.3 mM Ca2+. Dialysis with 1 mM of the low-affinity chelators 2-amino-5-fluorophenol-N,N,O-triacetic acid (5-fluoro APTRA) or 5,5'-dinitro BAPTA had no apparent effect on IsAHP. All of the chelators that prolonged the decay phase of IsAHP also induced a rising phase such that a well-defined peak of IsAHP could be discerned at approximately 0.6 s after the end of the stimulus used to evoke the current. 6. Weak stimulation of muscarinic receptors selectively inhibits IsAHP. Thus the uncontaminated time course of IsAHP can be deduced by subtracting currents recorded before and after such muscarinic stimulation. Wit...

It is well known that interneurons are heterogeneous in their morphologies, biophysical properties, pharmacological sensitivities and electrophysiological responses, but it is unknown how best to understand this diversity. Given their critical roles in shaping brain output, it is important to try to understand the functionality of their computational characteristics. To do this, we focus on specific interneuron subtypes. In particular, it has recently been shown that long‐term potentiation is induced specifically on oriens‐lacunosum/moleculare (O‐LM) interneurons in hippocampus CA1 and that the same cells contain the highest density of dendritic sodium and potassium conductances measured to date. We have created multi‐compartment models of an O‐LM hippocampal interneuron using passive properties, channel kinetics, densities and distributions specific to this cell type, and explored its signalling characteristics. We found that spike initiation depends on both location and amount of input, as well as the intrinsic properties of the interneuron. Distal synaptic input always produces strong back‐propagating spikes whereas proximal input could produce both forward‐ and back‐propagating spikes depending on the input strength. We speculate that the highly active dendrites of these interneurons endow them with a specialized function within the hippocampal circuitry by allowing them to regulate direct and indirect signalling pathways within the hippocampus.

Aims/hypothesis Endoplasmic reticulum (ER) stress has been implicated in glucose-induced beta cell dysfunction. However, its causal role has not been established in vivo. Our objective was to determine the causal role of ER stress and its link to oxidative stress in glucose-induced beta cell dysfunction in vivo. Methods Healthy Wistar rats were infused i.v. with glucose for 48 h to achieve 20 mmol/l hyperglycaemia with or without the co-infusion of the superoxide dismutase mimetic tempol (TPO), or the chemical chaperones 4-phenylbutyrate (PBA) or tauroursodeoxycholic acid (TUDCA). This was followed by assessment of beta cell function and measurement of ER stress markers and superoxide in islets.Results Glucose infusion for 48 h increased mitochondrial superoxide and ER stress markers and impaired beta cell function. Co-infusion of TPO, which we previously found to reduce mitochondrial superoxide and prevent glucoseinduced beta cell dysfunction, reduced ER stress markers.Similar to findings with TPO, co-infusion of PBA, which decreases mitochondrial superoxide, prevented glucoseinduced beta cell dysfunction in isolated islets. TUDCA was also effective. Also similar to findings with TPO, PBA prevented beta cell dysfunction during hyperglycaemic clamps in vivo and after hyperglycaemia (15 mmol/l) for 96 h. Conclusions/interpretation Here, we causally implicate ER stress in hyperglycaemia-induced beta cell dysfunction in vivo. We show that: (1) there is a positive feedback cycle between oxidative stress and ER stress in glucose-induced beta cell dysfunction, which involves mitochondrial superoxide; and (2) this cycle can be interrupted by superoxide dismutase mimetics as well as chemical chaperones, which are of potential interest to preserve beta cell function in type 2 diabetes.

Much work now emphasizes the concept that interneuronal networks play critical roles in generating synchronized, oscillatory behavior. Experimental work has shown that functional inhibitory networks alone can produce synchronized activity, and theoretical work has demonstrated how synchrony could occur in mutually inhibitory networks. Even though gap junctions are known to exist between interneurons, their role is far from clear. We present a mechanism by which synchronized bursting can be produced in a minimal network of mutually inhibitory and gap-junctionally coupled neurons. The bursting relies on the presence of persistent sodium and slowly inactivating potassium currents in the individual neurons. Both GABAA inhibitory currents and gap-junctional coupling are required for stable bursting behavior to be obtained. Typically, the role of gap-junctional coupling is focused on synchronization mechanisms. However, these results suggest that a possible role of gap-junctional coupling may lie in the generation and stabilization of bursting oscillatory behavior.