Somatostatin-expressing-interneurons (SOMIs) in the dentate gyrus (DG) control formation of granule cell (GC) assemblies during memory acquisition. Hilar-perforant-path-associated interneurons (HIPP cells) have been considered to be synonymous for DG-SOMIs. Deviating from this assumption, we show two functionally contrasting DG-SOMI-types. The classical feedback-inhibitory HIPPs distribute axon fibers in the molecular layer. They are engaged by converging GC-inputs and provide dendritic inhibition to the DG circuitry. In contrast, SOMIs with axon in the hilus, termed hilar interneurons (HILs), provide perisomatic inhibition onto GABAergic cells in the DG and project to the medial septum. Repetitive activation of glutamatergic inputs onto HIPP cells induces long-lasting-depression (LTD) of synaptic transmission but long-term-potentiation (LTP) of synaptic signals in HIL cells. Thus, LTD in HIPPs may assist flow of spatial information from the entorhinal cortex to the DG, whereas LTP in HILs may facilitate the temporal coordination of GCs with activity patterns governed by the medial septum.DOI: http://dx.doi.org/10.7554/eLife.21105.001

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Even though it has been known for some time that in many mammalian brain areas interneurons are electrically coupled, a quantitative description of the network electrical connectivity and its impact on cellular passive properties is still lacking. Approaches used so far to solve this problem are limited because they do not readily distinguish junctions among direct neighbors from indirect junctions involving intermediary, multiply connected cells. In the cerebellar cortex, anatomical and functional evidence indicates electrical coupling between molecular layer interneurons (basket and stellate cells). An analysis of the capacitive currents obtained under voltage clamp in molecular layer interneurons of juvenile rats or mice reveals an exponential component with a time constant of ∼20 ms, which represents capacitive loading of neighboring cells through gap junctions. These results, taken together with dual cell recording of electrical synapses, have led us to estimate the number of direct neighbors to be ∼4 for rat basket cells and ∼1 for rat stellate cells. The weighted number of neighbors (number of neighbors, both direct and indirect, weighted with the percentage of voltage deflection at steady state) was 1.69 in basket cells and 0.23 in stellate cells. The last numbers indicate the spread of potential changes in the network and serve to estimate the contribution of gap junctions to cellular input conductance. In conclusion the present work offers effective tools to analyze the connectivity of electrically connected interneuron networks, and it indicates that in juvenile rodents, electrical communication is stronger among basket cells than among stellate cells. To model the functional role of gap junctions (GJs) in the IN network and in cellular computation, it is necessary to determine the number of cells that are connected to a given cell, as well as the geometry of the network. Methods that have been developed to extract this information include dye coupling analysis (e.g., ref. 6), paired recordings coupled with anatomical descriptions (7), and frequency-dependent impedance measurements (8). The first two methods do not readily distinguish direct connections from indirect connections involving an intermediate IN (7,9,10), and all three methods are labor intensive and difficult to implement in a fully quantitative manner. In addition, they do not provide information on the spatial arrangement of the GJs. Therefore, the data that have been exploited for modeling GJ connectivity in IN networks are missing critical elements.In the cerebellum, Golgi cells and molecular layer interneurons (MLIs) have been shown to form anatomical and functional networks involving GJs that are specific to a given cell type (6,(11)(12)(13)(14). In both cases GJs may be involved in the generation of concerted oscillations under some pharmacological conditions (12, 15), and spikelets (spikes of coupled cells filtered through GJs) have been shown to encode sensory information in MLIs (16). MLIs are particularly interesting because th...

Cell-attached recording is extensively used to study the firing rate of mammalian neurons, but potential limitations of the method have not been investigated in detail. Here we perform cell-attached recording of molecular layer interneurons in cerebellar slices from rats and mice, and we study how experimental conditions influence the measured firing rate. We find that this rate depends on time in cellattached mode, on pipette potential, and on pipette ionic composition. In the first minute after sealing, action currents are variable in shape and size, presumably reflecting membrane instability. The firing rate remains approximately constant during the first 4 min after sealing and gradually increases afterward. Making the pipette potential more positive leads to an increase in the firing rate, with a steeper dependence on voltage if the pipette solution contains K ϩ as the main cation than if it contains Na ϩ . Ca 2ϩ imaging experiments show that establishing a cell-attached recording can result in an increased somatic Ca 2ϩ concentration, reflecting an increased firing rate linked to an increase in the pipette-cell conductance. Pipette effects on cell firing are traced to a combination of passive electrical coupling, opening of voltage-and Ca 2ϩ -sensitive K ϩ channels (BK channels) after action potentials, and random activation of voltageinsensitive, presumably mechanosensitive, cationic channels. We conclude that, unless experimental conditions are optimized, cellattached recordings in small neurons may report erroneous firing rates.

Connexin43 (Cx43) is widely expressed in embryonic brain, and its expression becomes restricted mainly to astrocytes as the central nervous system matures. Recent studies have indicated that Cx43 plays important, nonchannel, roles during central nervous system development by affecting neuronal cell migration. Here, we evaluated the effects of Cx43 on neuronal differentiation. For that we used an in vitro model of neural cell development (neurospheres) to evaluate, through immunocytochemistry, electrophysiology, and molecular biology, the degree of neuronal maturation from neurospheres derived from wild-type (WT) and Cx43-null mice. Our results indicate that Cx43 is a negative modulator of neuronal differentiation. The percent neurospheres containing differentiated neurons and the number of cells displaying inward currents were significantly higher in Cx43-null than in WT littermate neurospheres. Knockdown of Cx43 with small interfering RNA increased the number of WT neurospheres generating differentiated neurons. Blockade of gap junctional communication with carbenoxolone did not induce neuronal differentiation in WT neurospheres. Transfection of Cx43-null neurospheres with Cx43 mutants revealed that Cx43 carboxyl terminus prevents neuronal maturation. In agreement with these in vitro data, in situ analysis of embryonic day 16 brains revealed increased ␤-III-tubulin expression in germinal zones of Cx43-null compared with that of WT littermates. These results indicate that Cx43, and specifically its carboxyl terminus, is crucial for signaling mechanisms preventing premature neuronal differentiation during embryonic brain development.Multiple distinct mechanisms contribute to neocortical development. Diffusible and nondiffusible molecules have been implicated in neural cell proliferation, migration, and differentiation during brain development (1-4). Connexins (Cx), 2 the proteins forming gap junctions, are prominent in neural progenitor cells and play important roles in neural cell proliferation, migration, and differentiation (5-9). Among the central nervous system gap junction proteins, Cx43 and Cx26 are the two most abundantly expressed in neural stem cells, although transcripts for other connexins (Cx29, Cx30, Cx30.2, Cx32, Cx36, and Cx47) are also present in embryonic states (10 -12). The expression pattern of connexin proteins dramatically changes as the central nervous system matures, becoming restricted with respect to cell type. For instance, following postnatal development, Cx43 together with Cx30 are mainly found in astrocytes, whereas Cx29, Cx32, and Cx47 form the oligodendrocyte group of gap junction proteins, and Cx36, Cx45, and Cx30.2 are expressed in neurons (for review, see Ref. 13).The dramatic decrease in Cx43 expression during central nervous system development, specifically during neuroblast maturation, has raised the possibility that concurrent loss of gap junctional communication may play an important role during neuronal differentiation. Indeed, initial studies (14, 15) indicating an inver...

Axons functionally link the somato-dendritic compartment to synaptic terminals. Structurally and functionally diverse, they accomplish a central role in determining the delays and reliability with which neuronal ensembles communicate. By combining their active and passive biophysical properties, they ensure a plethora of physiological computations. In this review, we revisit the biophysics of generation and propagation of electrical signals in the axon and their dynamics. We further place the computational abilities of axons in the context of intracellular and intercellular coupling. We discuss how, by means of sophisticated biophysical mechanisms, axons expand the repertoire of axonal computation, and thereby, of neural computation.

Electrical synapses are ubiquitous in interneuron networks. They form intercellular pathways, allowing electrical currents to leak between coupled interneurons. I explored the impact of electrical coupling on the integration of excitatory signals and on the coincidence detection abilities of electrically-coupled cerebellar basket cells (BCs). In order to do so, I quantified the influence of electrical coupling on the rate, the probability and the latency at which BCs generate action potentials when stimulated. The long-lasting simultaneous suprathreshold depolarization of a coupled cell evoked an increase in firing rate and a shortening of action potential latency in a reference basket cell, compared to its depolarization alone. Likewise, the action potential probability of coupled cells was strongly increased when they were simultaneously stimulated with trains of short-duration near-threshold current pulses (mimicking the activation of presynaptic granule cells) at 10 Hz, and to a lesser extent at 50 Hz, an effect that was absent in non-coupled cells. Moreover, action potential probability was increased and action potential latency was shortened in response to synaptic stimulations in mice lacking the protein that forms gap junctions between BCs, connexin36, relative to wild-type (WT) controls. These results suggest that electrical synapses between BCs decrease the probability and increase the latency of stimulus-triggered action potentials, both effects being reverted upon simultaneous excitation of coupled cells. Interestingly, varying the delay at which coupled cells are stimulated revealed that the probability and the speed of action potential generation are facilitated maximally when a basket cell is stimulated shortly after a coupled cell. These findings suggest that electrically-coupled interneurons behave as coincidence and sequence detectors that dynamically regulate the latency and the strength of inhibition onto postsynaptic targets depending on the degree of input synchrony in the coupled interneuron network.

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