Previous work indicates

that stimulation of the alveus evokes at least two forms of recurrent inhibition, with a single stimulus recruiting primarily somatic and proximal dendritic inhibition, whereas brief trains (as used in the study by Müller and colleagues) also recruit a distal dendritic form of inhibition mediated by stratum oriens and lacunosum-moleculare (OL-M) cells ( Pouille and Scanziani, 2004). The somatic and proximal dendritic inhibition evoked by alveus stimulation is likely to be mediated by a variety of interneuron subtypes, including axo-axonic selleck compound cells, which target the axon initial segment, basket cells, which are primarily somatic, and bistratified cells, which target oblique and basal dendrites ( Somogyi and Klausberger, 2005). To generate dendritic spikes, the authors use local glutamate iontophoresis targeted to oblique and basal dendritic branches. Consistent with earlier work using glutamate uncaging (Losonczy et al., 2008), they find that glutamate iontophoresis generates localized dendritic spikes in a subset of basal and apical oblique branches of hippocampal CA1 pyramidal neurons. These

local dendritic spikes can be detected at the soma as an abrupt change in the rate of rise of the somatic membrane potential, and they had similar properties to events generated by glutamate uncaging or www.selleckchem.com/products/Paclitaxel(Taxol).html local synaptic stimulation. Presumably the authors chose to use glutamate iontophoresis rather than uncaging in these experiments because of the capacity of caged glutamate to block GABA receptors (Fino et al., 2009). As observed previously (Losonczy et al., 2008), the authors find that these dendritic spikes come in two classes, weak and strong, with strong Calpain dendritic spikes more effective in generating action potential output. The main new finding from the study (Müller et al., 2012) is that while recurrent inhibition is effective in blocking the

generation of weak dendritic spikes, it is ineffective in blocking the generation of strong dendritic spikes. The authors go on to show that this is also the case after conversion of weak dendritic spikes to strong dendritic spikes following the pairing of dendritic spikes with bursts of somatic action potentials. Finally, the authors investigate the impact of recurrent inhibition during theta-burst stimulation, used to mimic the natural theta rhythm, showing that an activity-dependent reduction in inhibition during theta-burst stimulation reduces the capacity of inhibition to block the generation of dendritic spikes. The data show that recurrent inhibition is relatively ineffective in blocking the generation of strong dendritic spikes, which begs the question: What is it about these events that makes them so powerful? Previous work indicates an important role of dendritic A-type potassium channels in regulating the strength of localized dendritic spikes in hippocampal CA1 pyramidal neurons (Losonczy et al., 2008).