Dravet syndrome is a severe, childhood-onset epilepsy largely due to heterozygous loss-of-function mutation of the gene , which encodes the type 1 neuronal voltage-gated sodium (Na) channel α subunit Nav1.1. Prior studies in mouse models of Dravet syndrome ( mice) indicate that, in cerebral cortex, Nav1.1 is predominantly expressed in GABAergic interneurons, in particular in parvalbumin-positive fast-spiking basket cell interneurons (PVINs). This has led to a model of Dravet syndrome pathogenesis in which Nav1.1 mutation leads to preferential dysfunction of interneurons, decreased synaptic inhibition, hyperexcitability, and epilepsy. However, such studies have been implemented at early developmental time points. Here, we performed electrophysiological recordings in acute brain slices prepared from male and female mice as well as age-matched wild-type littermate controls and found that, later in development, the excitability of PVINs had normalized. Analysis of action potential waveforms indirectly suggests a reorganization of axonal Na channels in PVINs from mice, a finding supported by immunohistochemical data showing elongation of the axon initial segment. Our results imply that transient impairment of action potential generation by PVINs may contribute to the initial appearance of epilepsy, but is not the mechanism of ongoing, chronic epilepsy in Dravet syndrome. Dravet syndrome is characterized by normal early development, temperature-sensitive seizures in infancy, progression to treatment-resistant epilepsy, developmental delay, autism, and sudden unexplained death due to mutation in encoding the Na+ channel subunit Nav1.1. Prior work has revealed a preferential impact of Nav1.1 loss on the function of GABAergic inhibitory interneurons. However, such data derive exclusively from recordings of neurons in young mice. Here, we show that impaired action potential generation observed in parvalbumin-positive fast-spiking interneurons (PVINs) in+/- mice during early development has normalized by postnatal day 35. This work suggests that a transient impairment of PVINs contributes to epilepsy onset, but is not the mechanism of ongoing, chronic epilepsy in Dravet syndrome.
Nerve impulse activity produces both developmental and adult plastic changes in neural networks. For development, however, its precise role and the mechanisms involved remain elusive. Using the classic model of synapse competition and elimination at newly formed neuromuscular junctions, we asked whether spike timing is the instructive signal at inputs competing for synaptic space. Using a rat strain whose soleus muscle is innervated by two nerves, we chronically evoked different temporal spike patterns in the two nerves during synapse formation in the adult. We found that asynchronous activity imposed upon the two nerves promotes synapse elimination, provided that their relative spikes are separated by 25 ms or more; remarkably, this elimination occurs even though an equal number of spikes were evoked in the competing axons. On the other hand, when spikes are separated by 20 ms or less, activity is perceived as synchronous, and elimination is prevented. Thus, in development, as in adult plasticity, precise spike timing plays an instructive role in synaptic modification.I n the adult brain, plastic changes in the strength of synaptic connections between excitable cells occur as a result of experience and contribute to shaping its architecture during development. Many of these changes are known to be tightly linked to the pattern of action potential firing. Temporal spike correlation in pre-and postsynaptic cells strengthens or weakens synapses during development (1-3) and in cellular models of learning (long-term potentiation and depression) (4, 5). Two well known paradigms for these phenomena are Hebb's postulate (6) and spike-timing-dependent plasticity (STDP) (7-10). A classic model to investigate synaptic modification is the elimination of input that occurs at developing neuromuscular junctions (NMJs) as a result of competition among the motor nerve terminals (11)(12)(13)(14). Elimination of input is widespread in the developing peripheral nervous system and CNS; at the NMJ, where it was identified (13), it spans the first 2 wk of postnatal life in rodents, during which time the innervation of each muscle fiber changes from innervation by the collaterals of different motor neurons (polyneuronal innervation) to innervation by only one collateral (mononeuronal innervation). Examples of this peculiar end result also are observed in the CNS (e.g., the innervation of Purkinje cells by climbing fibers) (15). Activity influences this process, but its precise role remains controversial. Briefly, some studies emphasize the overall neuromuscular activity, others emphasize the differences in the amount of activity in competing inputs, and still other studies emphasize activity-independent factors (16-27). (We explore this controversy in more detail in the Discussion.)Differences in activity generally have been tested by comparing active inputs with inputs completely inactivated by conduction block. However, the insight gained from these experiments is limited because all competing motor terminals are active during norma...
During behavioral quiescence, such as slow-wave sleep and anesthesia, the neocortex is in a deactivated state characterized by the presence of slow oscillations. During arousal, slow oscillations are absent and the neocortex is in an activated state that greatly impacts information processing. Neuromodulators acting in neocortex are believed to mediate these state changes, but the mechanisms are poorly understood. We investigated the actions of noradrenergic and cholinergic activation on slow oscillations, cellular excitability, and synaptic inputs in thalamocortical slices of somatosensory cortex. The results show that neuromodulation abolishes slow oscillations, dampens the excitability of principal cells, and rebalances excitatory and inhibitory synaptic inputs in thalamocortical-recipient layers IV-III. Sensory cortex is much more selective about the inputs that can drive it. The source of neuromodulation is critically important in determining this selectivity. Cholinergic activation suppresses the excitatory and inhibitory conductances driven by thalamocortical and intracortical inputs. Noradrenergic activation suppresses the excitatory conductance driven by intracortical inputs but not by thalamocortical inputs and enhances the inhibitory conductance driven by thalamocortical inputs but not by intracortical inputs. Thus noradrenergic activation emphasizes thalamocortical (sensory) inputs relative to intracortical inputs, while cholinergic activation suppresses both. slow oscillation; thalamocortical slice; thalamus; Up and Down states; acetylcholine; norepinephrine THE THALAMUS AND NEOCORTEX generate a variety of electrical activities during different behavioral states that have profound consequences on signals flowing through them. During slowwave sleep and anesthesia, cortical networks are typically in a so-called deactivated or synchronized state that consists of spontaneous "slow oscillations," which are characterized by rhythmic cycles of synaptically mediated depolarization and increased firing (Up states) followed by a decrease of synaptic inputs leading to membrane hyperpolarization and cessation of firing (Down states) (Cowan and Wilson 1994;
Rodents use their whiskers to explore the environment, and the superior colliculus is part of the neural circuits that process this sensorimotor information. Cells in the intermediate layers of the superior colliculus integrate trigeminotectal afferents from trigeminal complex and corticotectal afferents from barrel cortex. Using histological methods in mice, we found that trigeminotectal and corticotectal synapses overlap somewhat as they innervate the lower and upper portions of the intermediate granular layer, respectively. Using electrophysiological recordings and optogenetics in anesthetized mice in vivo, we showed that, similar to rats, whisker deflections produce two successive responses that are driven by trigeminotectal and corticotectal afferents. We then employed in vivo and slice experiments to characterize the response properties of these afferents. In vivo, corticotectal responses triggered by electrical stimulation of the barrel cortex evoke activity in the superior colliculus that increases with stimulus intensity and depresses with increasing frequency. In slices from adult mice, optogenetic activation of channelrhodopsin-expressing trigeminotectal and corticotectal fibers revealed that cells in the intermediate layers receive more efficacious trigeminotectal, than corticotectal, synaptic inputs. Moreover, the efficacy of trigeminotectal inputs depresses more strongly with increasing frequency than that of corticotectal inputs. The intermediate layers of superior colliculus appear to be tuned to process strong but infrequent trigeminal inputs and weak but more persistent cortical inputs, which explains features of sensory responsiveness, such as the robust rapid sensory adaptation of whisker responses in the superior colliculus.
Migraine is a complex brain disorder, characterized by attacks of unilateral headache and global dysfunction in multisensory information processing, whose underlying cellular and circuit mechanisms remain unknown. The finding of enhanced excitatory, but unaltered inhibitory, neurotransmission at intracortical synapses in mouse models of familial hemiplegic migraine (FHM) suggested the hypothesis that dysregulation of the excitatory-inhibitory balance in specific circuits is a key pathogenic mechanism. Here, we investigated the thalamocortical (TC) feedforward inhibitory microcircuit in FHM1 mice of both sexes carrying a gain-of-function mutation in Ca V 2.1. We show that TC synaptic transmission in somatosensory cortex is enhanced in FHM1 mice. Due to similar gain of function of TC excitation of layer 4 excitatory and fast-spiking inhibitory neurons elicited by single thalamic stimulations, neither the excitatory-inhibitory balance nor the integration time window set by the TC feedforward inhibitory microcircuit was altered in FHM1 mice. However, during repetitive thalamic stimulation, the typical shift of the excitatory-inhibitory balance toward excitation and the widening of the integration time window were both smaller in FHM1 compared with WT mice, revealing a dysregulation of the excitatory-inhibitory balance, whereby the balance is relatively skewed toward inhibition. This is due to an unexpected differential effect of the FHM1 mutation on short-term synaptic plasticity at TC synapses on cortical excitatory and fast-spiking inhibitory neurons. Our findings point to enhanced transmission of sensory, including trigeminovascular nociceptive, signals from thalamic nuclei to cortex and TC excitatory-inhibitory imbalance as mechanisms that may contribute to headache, increased sensory gain, and sensory processing dysfunctions in migraine.
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