Boosting of Synaptic Potentials and Spine Ca Transients by the Peptide Toxin SNX-482 Requires Alpha-1E-Encoded Voltage-Gated Ca Channels

The majority of glutamatergic synapses formed onto principal neurons of the mammalian central nervous system are associated with dendritic spines. Spines are tiny protuberances that house the proteins that mediate the response of the postsynaptic cell to the presynaptic release of glutamate. Postsynaptic signals are regulated by an ion channel signaling cascade that is active in individual dendritic spines and involves voltage-gated calcium (Ca) channels, small conductance (SK)-type Ca-activated potassium channels, and NMDA-type glutamate receptors. Pharmacological studies using the toxin SNX-482 indicated that the voltage-gated Ca channels that signal within spines to open SK channels belong to the class CaV2.3, which is encoded by the Alpha-1E pore-forming subunit. In order to specifically test this conclusion, we examined the effects of SNX-482 on synaptic signals in acute hippocampal slices from knock-out mice lacking the Alpha-1E gene. We find that in these mice, application of SNX-482 has no effect on glutamate-uncaging evoked synaptic potentials and Ca influx, indicating that that SNX-482 indeed acts via the Alpha-1E-encoded CaV2.3 channel

Control of Ca2+ Influx and Calmodulin Activation by SK-Channels in Dendritic Spines

© 2016 Griffith et al. The key trigger for Hebbian synaptic plasticity is influx of Ca2+ into postsynaptic dendritic spines. The magnitude of [Ca2+] increase caused by NMDA-receptor (NMDAR) and voltage-gated Ca2+ -channel (VGCC) activation is thought to determine both the amplitude and direction of synaptic plasticity by differential activation of Ca2+ -sensitive enzymes such as calmodulin. Ca2+ influx is negatively regulated by Ca2+ -activated K+ channels (SK-channels) which are in turn inhibited by neuromodulators such as acetylcholine. However, the precise mechanisms by which SK-channels control the induction of synaptic plasticity remain unclear. Using a 3-dimensional model of Ca2+ and calmodulin dynamics within an idealised, but biophysically-plausible, dendritic spine, we show that SK-channels regulate calmodulin activation specifically during neuron-firing patterns associated with induction of spike timing-dependent plasticity. SK-channel activation and the subsequent reduction in Ca2+ influx through NMDARs and L-type VGCCs results in an order of magnitude decrease in calmodulin (CaM) activation, providing a mechanism for the effective gating of synaptic plasticity induction. This provides a common mechanism for the regulation of synaptic plasticity by neuromodulators

Inhibition of Post-Synaptic Kv7/KCNQ/M Channels Facilitates Long-Term Potentiation in the Hippocampus

Activation of muscarinic acetylcholine receptors (mAChR) facilitates the induction of synaptic plasticity and enhances cognitive function. In the hippocampus, M1 mAChR on CA1 pyramidal cells inhibit both small conductance Ca2+-activated KCa2 potassium channels and voltage-activated Kv7 potassium channels. Inhibition of KCa2 channels facilitates long-term potentiation (LTP) by enhancing Ca2+calcium influx through postsynaptic NMDA receptors (NMDAR). Inhibition of Kv7 channels is also reported to facilitate LTP but the mechanism of action is unclear. Here, we show that inhibition of Kv7 channels with XE-991 facilitated LTP induced by theta burst pairing at Schaffer collateral commissural synapses in rat hippocampal slices. Similarly, negating Kv7 channel conductance using dynamic clamp methodologies also facilitated LTP. Negation of Kv7 channels by XE-991 or dynamic clamp did not enhance synaptic NMDAR activation in response to theta burst synaptic stimulation. Instead, Kv7 channel inhibition increased the amplitude and duration of the after-depolarisation following a burst of action potentials. Furthermore, the effects of XE-991 were reversed by re-introducing a Kv7-like conductance with dynamic clamp. These data reveal that Kv7 channel inhibition promotes NMDAR opening during LTP induction by enhancing depolarisation during and after bursts of postsynaptic action potentials. Thus, during the induction of LTP M1 mAChRs enhance NMDAR opening by two distinct mechanisms namely inhibition of KCa2 and Kv7 channels

Selective Phosphorylation Modulates the PIP2 Sensitivity of the CaM-SK Channel Complex

Phosphatidylinositol bisphosphate (PIP2) regulates the activities of many membrane proteins including ion channels through direct interactions. However, the affinity of PIP2 is so high for some channel proteins that its physiological role as a modulator has been questioned. Here we show that PIP2 is an important cofactor for activation of small conductance Ca2+-activated potassium channels (SK) by Ca2+-bound calmodulin (CaM). Removal of the endogenous PIP2 inhibits SK channels. The PIP2-binding site resides at the interface of CaM and the SK C-terminus. We further demonstrate that the affinity of PIP2 for its target proteins can be regulated by cellular signaling. Phosphorylation of CaM T79, located adjacent to the PIP2-binding site, by Casein Kinase 2 reduces the affinity of PIP2 for the CaM-SK channel complex by altering the dynamic interactions among amino acid residues surrounding the PIP2-binding site. This effect of CaM phosphorylation promotes greater channel inhibition by G-protein-mediated hydrolysis of PIP2

Olfactory and haptic crossmodal perception in a visual recognition task

Olfactory perception is affected by cross-modal interactions between different senses. However, although the effect of cross-modal interactions for smell have been well investigated, little attention has been paid to the facilitation expressed by haptic interactions with a manipulation of the odorous object’s shape. The aim of this research is to investigate whether there is a cortical modulation in a visual recognition task if the stimulus is processed through an odorous cross-modal pathway or by haptic manipulation, and how these interactions may have an influence on early visual-recognition patterns. Ten healthy non-smoking subjects (25 years ± 5 years) were trained to have a haptic manipulation of 3-D models and olfactory stimulation. Subsequently, a visual recognition task was performed during an electroencephalography recording to investigate the P3 Event Related Potentials components. The subjects had to respond on the keyboard according to their subjective predominant recognition (olfactory or haptic). The effects of haptic and olfactory condition were assessed via linear mixed-effects models (LMMs) of the lme4 package. This model allows for the variance related to random factors to be controlled without any data aggregation. The main results highlighted that P3 increased in the olfactory cross-modal condition, with a significant two-way interaction between odor and left-sided lateralization. Furthermore, our results could be interpreted according to ventral and dorsal pathways as favorite ways to olfactory crossmodal perception

Olfactory and haptic crossmodal perception in a visual recognition task

Olfactory perception is affected by cross-modal interactions between different senses. However, although the effect of cross-modal interactions for smell have been well investigated, little attention has been paid to the facilitation expressed by haptic interactions with a manipulation of the odorous object’s shape. The aim of this research is to investigate whether there is a cortical modulation in a visual recognition task if the stimulus is processed through an odorous cross-modal pathway or by haptic manipulation, and how these interactions may have an influence on early visual-recognition patterns. Ten healthy non-smoking subjects (25 years ± 5 years) were trained to have a haptic manipulation of 3-D models and olfactory stimulation. Subsequently, a visual recognition task was performed during an electroencephalography recording to investigate the P3 Event Related Potentials components. The subjects had to respond on the keyboard according to their subjective predominant recognition (olfactory or haptic). The effects of haptic and olfactory condition were assessed via linear mixed-effects models (LMMs) of the lme4 package. This model allows for the variance related to random factors to be controlled without any data aggregation. The main results highlighted that P3 increased in the olfactory cross-modal condition, with a significant two-way interaction between odor and left-sided lateralization. Furthermore, our results could be interpreted according to ventral and dorsal pathways as favorite ways to olfactory crossmodal perception