Selective activation of BK channels in small-headed dendritic spines suppresses excitatory postsynaptic potentials

Dendritic spines are the main receptacles of excitatory information in the brain. Their particular morphology, with a small head connected to the dendrite by a slender neck, has inspired theoretical and experimental work to understand how these structural features affect the processing, storage and integration of synaptic inputs in pyramidal neurons (PNs).The activation of glutamate receptors in spines triggers a large voltage change as well as calcium signals at the spine head. Thus, voltage-gated and calcium-activated potassium channels located in the spine head likely play a key role in synaptic transmission. Here we study the presence and function of large conductance calcium-activated potassium (BK) channels in spines from layer 5 PNs. We find that BK channels are localized to dendrites and spines regardless of their size, but their activity can only be detected in spines with small head volumes (≤ 0.09 µm3), which reduces the amplitude of two-photon (2P) uncaging (u) excitatory postsynaptic potentials (EPSPs) recorded at the soma. In addition, we find that calcium signals in spines with small head volumes are significantly larger than those observed in spines with larger head volumes. In accordance with our experimental data, numerical simulations predict that synaptic inputs impinging onto spines with small head volumes generate voltage responses and calcium signals within the spine head itself that are significantly larger than those observed in spines with bigger head volumes, which are sufficient to activate spine BK channels. These results show that BK channels are selectively activated in small-headed spines, suggesting a new level of dendritic spine-mediated regulation of synaptic processing, integration, and plasticity in cortical PNs.

Cholinergic and Noradrenergic Modulation of Corticothalamic Synaptic Input From Layer 6 to the Posteromedial Thalamic Nucleus in the Rat

Cholinergic and noradrenergic neuromodulation of the synaptic transmission from cortical layer 6 of the primary somatosensory cortex to neurons in the posteromedial thalamic nucleus (PoM) was studied using an in vitro slice preparation from young rats. Cholinergic agonist carbachol substantially decreased the amplitudes of consecutive excitatory postsynaptic potentials (EPSPs) evoked by a 20 Hz five pulse train. The decreased amplitude effect was counteracted by a parallel increase of synaptic frequency-dependent facilitation. We found this modulation to be mediated by muscarinic acetylcholine receptors. In the presence of carbachol the amplitudes of the postsynaptic potentials showed a higher trial-to-trial coefficient of variation (CV), which suggested a presynaptic site of action for the modulation. To substantiate this finding, we measured the failure rate of the excitatory postsynaptic currents in PoM cells evoked by “pseudominimal” stimulation of corticothalamic input. A higher failure-rate in the presence of carbachol indicated decreased probability of transmitter release at the synapse. Activation of the noradrenergic modulatory system that was mimicked by application of norepinephrine did not affect the amplitude of the first EPSP evoked in the five-pulse train, but later EPSPs were diminished. This indicated a decrease of the synaptic frequency-dependent facilitation. Treatment with noradrenergic α-2 agonist clonidine, α-1 agonist phenylephrine, or β-receptor agonist isoproterenol showed that the modulation may partly rely on α-2 adrenergic receptors. CV analysis did not suggest a presynaptic action of norepinephrine. We conclude that cholinergic and noradrenergic modulation act as different variable dynamic controls for the corticothalamic mechanism of the frequency-dependent facilitation in PoM.

A model of the CA1 field rhythms

We propose a model of the main rhythms in the hippocampal CA1 field: theta rhythm, slow, middle, and fast gamma rhythms, and ripples oscillations. We have based this on data obtained from animals behaving freely. We have considered the modes of neuronal discharges and the occurrence of local field potential (LFP) oscillations in the theta and non-theta states at different inputs from the CA3 field, the medial entorhinal cortex, and the medial septum. In our work, we tried to reproduce the main experimental phenomena about rhythms in the CA1 field: the coupling of neurons to the phase of rhythms, cross-rhythm phase-phase and phase-amplitude coupling. Using computational experiments, we have proved the hypothesis that the descending phase of the theta rhythm in the CA1 field is formed by the input from the CA3 field via the Shaffer collaterals, and the ascending phase of the theta rhythm is formed by the inhibitory postsynaptic potentials from CCK basket cells. The slow gamma rhythm is coupled to the descending phase of the theta rhythm, since it also depends on the arrival of the signal via the Shaffer collaterals. The middle gamma rhythm is formed by the excitatory postsynaptic potentials of the principal neurons of the third layer of the entorhinal cortex, corresponds to experimental data. We were able to unite in a single mathematical model several theoretical ideas about the mechanisms of rhythmic processes in the CA1 field of the hippocampus.

Spinal GABAergic neurons are under feed-forward inhibitory control driven by Aδ and C fibers in Gad2 td-Tomato mice

Background Spinal GABAergic neurons act as a critical modulator in sensory transmission like pain or itch. The monosynaptic or polysynaptic primary afferent inputs onto GABAergic neurons, along with other interneurons or projection neurons make up the direct and feed-forward inhibitory neural circuits. Previous research indicates that spinal GABAergic neurons mainly receive excitatory inputs from Aδ and C fibers. However, whether they are controlled by other inhibitory sending signals is not well understood. Methods We applied a transgenic mouse line in which neurons co-expressed the GABA-synthesizing enzyme Gad65 and the enhanced red fluorescence (td-Tomato) to characterize the features of morphology and electrophysiology of GABAergic neurons. Patch-clamp whole cell recordings were used to record the evoked postsynaptic potentials of fluorescent neurons in spinal slices in response to dorsal root stimulation. Results We demonstrated that GABAergic neurons not only received excitatory drive from peripheral Aβ, Aδ and C fibers, but also received inhibitory inputs driven by Aδ and C fibers. The evoked inhibitory postsynaptic potentials (eIPSPs) mediated by C fibers were mainly Glycinergic (66.7%) as well as GABAergic mixed with Glycinergic (33.3%), whereas the inhibition mediated by Aδ fibers was predominately both GABA and Glycine-dominant (57.1%), and the rest of which was purely Glycine-dominant (42.9%). Conclusion These results indicated that spinal GABAergic inhibitory neurons are under feedforward inhibitory control driven by primary C and Aδ fibers, suggesting that this feed-forward inhibitory pathway may play an important role in balancing the excitability of GABAergic neurons in spinal dorsal horn.

Essential Functions of the Transcription Factor Npas4 in Neural Circuit Development, Plasticity, and Diseases

Signaling from the synapse to nucleus is mediated by the integration and propagation of both membrane potential changes (postsynaptic potentials) and intracellular second messenger cascades. The electrical propagation of postsynaptic potentials allows for rapid neural information processing, while propagating second messenger pathways link synaptic activity to the transcription of genes required for neuronal survival and adaptive changes (plasticity) underlying circuit formation and learning. The propagation of activity-induced calcium signals to the cell nucleus is a major synapse-to-nucleus communication pathway. Neuronal PAS domain protein 4 (Npas4) is a recently discovered calcium-dependent transcription factor that regulates the activation of genes involved in the homeostatic regulation of excitatory–inhibitory balance, which is critical for neural circuit formation, function, and ongoing plasticity, as well as for defense against diseases such as epilepsy. Here, we summarize recent findings on the neuroprotective functions of Npas4 and the potential of Npas4 as a therapeutic target for the treatment of acute and chronic diseases of the central nervous system.

Stretchable elastic synaptic transistors for neurologically integrated soft engineering systems

Artificial synaptic devices that can be stretched similar to those appearing in soft-bodied animals, such as earthworms, could be seamlessly integrated onto soft machines toward enabled neurological functions. Here, we report a stretchable synaptic transistor fully based on elastomeric electronic materials, which exhibits a full set of synaptic characteristics. These characteristics retained even the rubbery synapse that is stretched by 50%. By implementing stretchable synaptic transistor with mechanoreceptor in an array format, we developed a deformable sensory skin, where the mechanoreceptors interface the external stimulations and generate presynaptic pulses and then the synaptic transistors render postsynaptic potentials. Furthermore, we demonstrated a soft adaptive neurorobot that is able to perform adaptive locomotion based on robotic memory in a programmable manner upon physically tapping the skin. Our rubbery synaptic transistor and neurologically integrated devices pave the way toward enabled neurological functions in soft machines and other applications.

Simulations of Learning, Memory, and Forgetting Processes with Model of CA1 Region of the Hippocampus

The aim of this paper is to present a computational model of the CA1 region of the hippocampus, whose properties include (a) attenuation of receptors for external stimuli, (b) delay and decay of postsynaptic potentials, (c) modification of internal weights due to propagation of postsynaptic potentials through the dendrite, and (d) modification of weights for the analog memory of each input due to a pattern of long-term synaptic potentiation (LTP) with regard to its decay. The computer simulations showed that CA1 model performs efficient LTP induction and high rate of sub-millisecond coincidence detection. We also discuss a possibility of hardware implementation of pyramidal cells of CA1 region of the hippocampus.