Protective Role of Low Ethanol Administration Following Ischemic Stroke via Recovery of KCC2 and p75NTR Expression.

A striking result from epidemiological studies show a correlation between low alcohol intake and lower incidence for ischemic stroke and severity of derived brain injury. Although reduced apoptosis and inflammation has been suggested to be involved, little is known about the mechanism mediating this effect in vivo. Increase in intracellular chloride concentration and derived depolarizing GABAAR-mediated transmission are common consequences following various brain injuries and are caused by the abnormal expression levels of the chloride cotransporters NKCC1 and KCC2. Downstream pro-apoptotic signaling through p75NTR may link GABAA depolarization with post-injury neuronal apoptosis. Here, we show that changes in GABAergic signaling, Cl- homeostasis, and expression of chloride cotransporters in the post-traumatic mouse brain can be significantly reduced by administration of 3% ethanol to the drinking water. Ethanol-induced upregulation of KCC2 has a positive impact on neuronal survival, preserving a large part of the cortical peri-infarct zone, as well as preventing the massive post-ischemic upregulation of the pro-apoptotic protein p75NTR. Importantly, intracortical multisite in vivo recordings showed that ethanol treatment could significantly ameliorate stroke-induced reduction in cortical activity. This surprising finding discloses a pathway triggered by low concentration of ethanol as a novel therapeutically relevant target.

The Kainate Receptor Subunit GluK2 Interacts With KCC2 to Promote Maturation of Dendritic Spines.

Kainate receptors (KAR) play a crucial role in the plasticity and functional maturation of glutamatergic synapses. However, how they regulate structural plasticity of dendritic spines is not known. The GluK2 subunit was recently shown to coexist in a functional complex with the neuronal K-Cl cotransporter KCC2. Apart from having a crucial role in the maturation of GABAergic transmission, KCC2 has a morphogenic role in the maturation of dendritic spines. Here, we show that in vivo local inactivation of GluK2 expression in CA3 hippocampal neurons induces altered morphology of dendritic spines and reduction in mEPSC frequency. GluK2 deficiency also resulted in a strong change in the subcellular distribution of KCC2 as well as a smaller somatodendritic gradient in the reversal potential of GABAA. Strikingly, the aberrant morphology of dendritic spines in GluK2-deficient CA3 pyramidal neurons was restored by overexpression of KCC2. GluK2 silencing in hippocampal neurons significantly reduced the expression of 4.1N and functional form of the actin filament severing protein cofilin. Consistently, assessment of actin dynamics using fluorescence recovery after photobleaching (FRAP) of ß-actin showed a significant increase in the stability of F-actin filaments in dendritic spines. In conclusion, our results demonstrate that GluK2-KCC2 interaction plays an important role in the structural maturation of dendritic spines. This also provides novel insights into the connection between KAR dysfunction, structural plasticity, and developmental disorders.

Revealing subthreshold motor contributions to perceptual confidence.

Established models of perceptual metacognition, the ability to evaluate our perceptual judgements, posit that perceptual confidence depends on the strength or quality of feedforward sensory evidence. However, alternative theoretical accounts suggest the entire perception-action cycle, and not only variation in sensory evidence, is monitored when evaluating confidence in one's percepts. Such models lead to the counterintuitive prediction that perceptual confidence should be directly modulated by features of motor output. To evaluate this proposal here we recorded electromyographic (EMG) activity of motor effectors while subjects performed a near-threshold perceptual discrimination task and reported their confidence in each response in a pre-registered experiment. A subset of trials exhibited subthreshold EMG activity in response effectors before a decision was made. Strikingly, trial-by-trial analysis showed that confidence, but not accuracy, was significantly higher on trials with subthreshold motor activation. These findings support a hypothesis that preparatory motor activity, or a related latent variable, impacts upon confidence over and above performance, consistent with models in which perceptual metacognition integrates information across the perception-action cycle.