The purpose of the present study was to develop sensitive, rapid, and easily quantified avoidance tests for small fish (Danio rerio) in order to provide important ecological information during toxicity assessments. Fish were exposed in three replicate linear flow-through chambers consisting of five compartments. The test system was found to provide a linear contamination gradient, with mean dilutions in each compartment of 90, 70, 50, 30, and 10%. Also, in the absence of a toxic gradient, the fish were uniformly distributed along the five-compartment chambers. Then the apparatus was evaluated by exposing fish to a concentration gradient of copper and a dilution gradient of a field sample contaminated with acid mine drainage (AMD). Avoidance was monitored at 24-h intervals up to 96 h of exposure. The avoidance of copper and AMD by D. rerio was confirmed. The apparatus enabled quantification of median avoidance effect concentrations or dilutions (EC50 or EDil50) and also lowest-observed-effect gradients, which express the minimum toxicant gradient eliciting avoidance, a parameter increasing the ecological relevance of the laboratory avoidance responses. For quantifying avoidance, a 24-h exposure was sufficient, as the 24- to 96-h EC50 and EDil50 values were similar. The avoidance response was easy and rapid to quantify, leading this test to routine use in environmental risk assessment.

Down syndrome (DS) results in various degrees of cognitive deficits. In DS mouse models, recovery of behavioral and neurophysiological deficits using GABAAR antagonists led to hypothesize an excessive activity of inhibitory circuits in this condition. Nonetheless, whether over-inhibition is present in DS and whether this is due to specific alterations of distinct GABAergic circuits is unknown. In the prefrontal cortex of Ts65Dn mice (a well-established DS model), we found that the dendritic synaptic inhibitory loop formed by somatostatin-positive Martinotti cells (MCs) and pyramidal neurons (PNs) was strongly enhanced, with no alteration in their excitability. Conversely, perisomatic inhibition from parvalbumin-positive (PV) interneurons was unaltered, but PV cells of DS mice lost their classical fast-spiking phenotype and exhibited increased excitability. These microcircuit alterations resulted in reduced pyramidal-neuron firing and increased phase locking to cognitive-relevant network oscillations in vivo. These results define important synaptic and circuit mechanisms underlying cognitive dysfunctions in DS.

The purpose of the present study was to develop sensitive, rapid, and easily quantified avoidance tests for small fish (Danio rerio) in order to provide important ecological information during toxicity assessments. Fish were exposed in three replicate linear flow-through chambers consisting of five compartments. The test system was found to provide a linear contamination gradient, with mean dilutions in each compartment of 90, 70, 50, 30, and 10%. Also, in the absence of a toxic gradient, the fish were uniformly distributed along the five-compartment chambers. Then the apparatus was evaluated by exposing fish to a concentration gradient of copper and a dilution gradient of a field sample contaminated with acid mine drainage (AMD). Avoidance was monitored at 24-h intervals up to 96 h of exposure. The avoidance of copper and AMD by D. rerio was confirmed. The apparatus enabled quantification of median avoidance effect concentrations or dilutions (EC50 or EDil50) and also lowest-observed-effect gradients, which express the minimum toxicant gradient eliciting avoidance, a parameter increasing the ecological relevance of the laboratory avoidance responses. For quantifying avoidance, a 24-h exposure was sufficient, as the 24- to 96-h EC50 and EDil50 values were similar. The avoidance response was easy and rapid to quantify, leading this test to routine use in environmental risk assessment.

In the neocortex, fast synaptic inhibition orchestrates both spontaneous and sensory-evoked activity. GABAergic interneurons (INs) inhibit pyramidal neurons (PNs) directly, modulating their output activity and thus contributing to balance cortical networks. Moreover, several IN subtypes also inhibit other INs, forming specific disinhibitory circuits, which play crucial roles in several cognitive functions. Here, we studied a homogeneous subpopulation of somatostatin (SST)-positive INs, the Martinotti cells (MCs) in layer 2/3 of the mouse barrel cortex (both sexes). MCs are a prominent IN subclass inhibiting the distal portion of PN apical dendrites, thus controlling dendrite electrogenesis and synaptic integration. Yet, it is poorly understood whether MCs inhibit other elements of the cortical circuits, and the connectivity properties with non-PN targets are unknown. We found that MCs have a strong preference for PN dendrites, but they also considerably connect with parvalbumin (PV)-positive, vasoactive intestinal peptide (VIP)-expressing and layer 1 (L1) INs. Remarkably, GABAergic synapses from MCs exhibited clear cell-type-specific short-term plasticity. Moreover, whereas the biophysical properties of MC-PN synapses were consistent with distal dendritic inhibition, MC-IN synapses exhibited characteristics of fast perisomatic inhibition. Finally, MC-PN connections used α5-containing GABAARs, but this subunit was not expressed by the other INs targeted by MCs. We reveal a specialized connectivity blueprint of MCs within different elements of superficial cortical layers. In addition, our results identify α5-GABAARs as the molecular fingerprint of MC-PN dendritic inhibition. This is of critical importance, given the role of α5-GABAARs in cognitive performance and their involvement in several brain diseases.

We thank the ICM technical facilities PHENO-ICMICE, iGENSEQ and ICM.Quant.

No abstract

Down syndrome (DS) results in various degrees of cognitive deficits. In DS mouse models, recovery of behavioral and neurophysiological deficits using GABAAR antagonists led to hypothesize an excessive activity of inhibitory circuits in this condition. Nonetheless, whether over-inhibition is present in DS and whether this is due to specific alterations of distinct GABAergic circuits is unknown. In the prefrontal cortex of Ts65Dn mice (a well-established DS model), we found that the dendritic synaptic inhibitory loop formed by somatostatin-positive Martinotti cells (MCs) and pyramidal neurons (PNs) was strongly enhanced, with no alteration of their excitability. Conversely, perisomatic inhibition from parvalbumin-positive (PV) interneurons was unaltered, but PV cells of DS mice lost their classical fast-spiking phenotype and exhibited increased excitability. These microcircuit alterations resulted in reduced pyramidal-neuron firing and increased phase locking to cognitive-relevant network oscillations in vivo. These results define important synaptic and circuit mechanisms underlying of cognitive dysfunctions in DS.

Down syndrome (DS) results in various degrees of cognitive deficits. In DS mouse models, recovery of behavioral and neurophysiological deficits using GABA A R antagonists led to hypothesize an excessive activity of inhibitory circuits in this condition. Nonetheless, whether over-inhibition is present in DS and whether this is due to specific alterations of distinct GABAergic circuits is unknown. In the prefrontal cortex of Ts65Dn mice (a well-established DS model), we found that the dendritic synaptic inhibitory loop formed by somatostatin-positive Martinotti cells (MCs) and pyramidal neurons (PNs) was strongly enhanced, with no alteration in their excitability. Conversely, perisomatic inhibition from parvalbumin-positive (PV) interneurons was unaltered, but PV cells of DS mice lost their classical fastspiking phenotype and exhibited increased excitability. These microcircuit alterations resulted in reduced pyramidal-neuron firing and increased phase locking to cognitive-relevant network oscillations in vivo. These results define important synaptic and circuit mechanisms underlying cognitive dysfunctions in DS.