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Na⁺-activated K⁺ (KNa) channels are expressed in neurons and are activated by Na⁺ influx through voltage-dependent channels or ionotropic receptors, yet their function remains unclear. Here we show that KNa channels are associated with AMPA receptors and that their activation depresses synaptic responses. Synaptic activation of KNa channels by Na⁺ transients via AMPA receptors shapes the decay of AMPA-mediated current as well as the amplitude of the synaptic potential. Thus, the coupling between KNa channels and AMPA receptors by synaptically induced Na⁺ transients represents an inherent negative feedback mechanism that scales down the magnitude of excitatory synaptic responses.

Here the authors demonstrate a causal role for the barrel cortex in the detection of single whisker stimuli. Whisker deflection evoked an early (<50 ms) reliable sensory response that was encoded through cell-specific reversal potentials. A secondary late (50–400 ms) depolarization was enhanced in hit trials compared to misses. Optogenetic inactivation revealed a causal role for late excitation. Neocortical activity can evoke sensory percepts, but the cellular mechanisms remain poorly understood. We trained mice to detect single brief whisker stimuli and report perceived stimuli by licking to obtain a reward. Pharmacological inactivation and optogenetic stimulation demonstrated a causal role for the primary somatosensory barrel cortex. Whole-cell recordings from barrel cortex neurons revealed membrane potential correlates of sensory perception. Sensory responses depended strongly on prestimulus cortical state, but both slow-wave and desynchronized cortical states were compatible with task performance. Whisker deflection evoked an early (<50 ms) reliable sensory response that was encoded through cell-specific reversal potentials. A secondary late (50–400 ms) depolarization was enhanced on hit trials compared to misses. Optogenetic inactivation revealed a causal role for late excitation. Our data reveal dynamic processing in the sensory cortex during task performance, with an early sensory response reliably encoding the stimulus and later secondary activity contributing to driving the subjective percept.

Na⁺-activated K⁺ $({\\rm K}_{{\\rm Na}})$ channels are expressed in neurons and are activated by Na⁺ influx through voltage-dependent channels or ionotropic receptors, yet their function remains unclear. Here we show that ${\\rm K}_{{\\rm Na}}$ channels are associated with AMPA receptors and that their activation depresses synaptic responses. Synaptic activation of ${\\rm K}_{{\\rm Na}}$ channels by Na⁺ transients via AMPA receptors shapes the decay of AMPA-mediated current as well as the amplitude of the synaptic potential. Thus, the coupling between ${\\rm K}_{{\\rm Na}}$ channels and AMPA receptors by synaptically induced Na⁺ transients represents an inherent negative feedback mechanism that scales down the magnitude of excitatory synaptic responses.

Na super(+)-activated K super(+) (K sub(Na)) channels are expressed in neurons and are activated by Na super(+) influx through voltage-dependent channels or ionotropic receptors, yet their function remains unclear. Here we show that K sub(Na) channels are associated with AMPA receptors and that their activation depresses synaptic responses. Synaptic activation of K sub(Na) channels by Na super(+) transients via AMPA receptors shapes the decay of AMPA-mediated current as well as the amplitude of the synaptic potential. Thus, the coupling between K sub(Na) channels and AMPA receptors by synaptically induced Na super(+) transients represents an inherent negative feedback mechanism that scales down the magnitude of excitatory synaptic responses.

Na...-activated K... (K...) channels are expressed in neurons and are activated by Na... influx through voltage-dependent channels or ionotropic receptors, yet their function remains unclear. Here we show that K... channels are associated with AMPA receptors and that their activation depresses synaptic responses. Synaptic activation of K... channels by Na... transients via AMPA receptors shapes the decay of AMPA-mediated current as well as the amplitude of the synaptic potential. Thus, the coupling between K... channels and AMPA receptors by synaptically induced Na... transients represents an inherent negative feedback mechanism that scales down the magnitude of excitatory synaptic responses. (ProQuest: ... denotes formulae/symbols omitted.)

Na⁺-activated K⁺ (KNa) channels are expressed in neurons and are activated by Na⁺ influx through voltage-dependent channels or ionotropic receptors, yet their function remains unclear. Here we show that KNa channels are associated with AMPA receptors and that their activation depresses synaptic responses. Synaptic activation of KNa channels by Na⁺ transients via AMPA receptors shapes the decay of AMPA-mediated current as well as the amplitude of the synaptic potential. Thus, the coupling between KNa channels and AMPA receptors by synaptically induced Na⁺ transients represents an inherent negative feedback mechanism that scales down the magnitude of excitatory synaptic responses.

Na + -activated K + (K Na ) channels are expressed in neurons and are activated by Na + influx through voltage-dependent channels or ionotropic receptors, yet their function remains unclear. Here we show that K Na channels are associated with AMPA receptors and that their activation depresses synaptic responses. Synaptic activation of K Na channels by Na + transients via AMPA receptors shapes the decay of AMPA-mediated current as well as the amplitude of the synaptic potential. Thus, the coupling between K Na channels and AMPA receptors by synaptically induced Na + transients represents an inherent negative feedback mechanism that scales down the magnitude of excitatory synaptic responses.

The overall objective of this thesis is to increase our understanding of neural networks generating locomotion. These networks called Central Pattern Generators (CPG), are localized in the spinal cord and cangenerate the basic locomotor pattern in the absence of sensory or supraspinal inputs. However, locomotor behaviour needs to be adapted to the changing environmental conditions, and this is proposed to be a result of neuromodulatory systems which can change the efficacy of synaptic transmission, and the intrinsic properties of CPG neurons. Thework presented here focuses on the role of metabotropic glutamatereceptors (mGluRs) in the spinal locomotor network. We show that a briefactivation of postsynaptic mGluR1 results in a long-term potentiation of the locomotor frequency associated with a long-term depression of the mid-cycle inhibition and potentiation of the on-cycle excitation. These effects are blocked by a cannabinoid receptor 1 (CB1) antagonists and nitric oxide synthase (NOS) inhibitors, suggesting that endocannabinoids and nitric oxide (NO) are involved. Overall, endocannabinoids and NO can shift the levels of excitation and inhibition, in favor of excitation to induce the long-term potentiation of the locomotor frequency. Endocannabinoids are released on demand following activation of mGluR1 at the postsynaptic site and inhibit presynaptic glycinergic transmission.This de novo retrograde signaling via endocannabinoids enables network neurons to control their synaptic input and thus the level of their activation. We show that 2-Arachydonylglycerol (2-AG) is the primaryendocannabinoid released by activation of mGluR1 and mediates the potentiation of the locomotor frequency and the associated depression of mid-cycle inhibition. In the lamprey spinal cord NOS is found in greymatter neurons and provides an intrinsic NO tone which enhances the locomotor frequency. NO increases the locomotor frequency by reducing mid-cycle inhibition via presynaptic mechanisms, and by increasing the excitatory drive via both pre-and postsynaptic mechanisms. Finally,endogenous activation of mGluR1, cannabinoid and NO signaling facilitates the excitatory drive underlying locomotion and thus contribute to the pattern generation within the spinal cord. The endogenous NO signaling is acting downstream CB1, while approximately 30% of the endocannabinoidtone is dependent on mGluR1 activation.In summary we propose novel modulatory signaling pathways within the spinal CPG and suggest that neuro modulation is a core process embedded within the CPG function that shapes the generation of locomotion.