Neuronal circuits overcome imbalance in excitation and inhibition by adjusting connection numbers.
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ABSTRACT:
SUBMITTER: Sukenik N
PROVIDER: S-EPMC8000583 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Excitation-inhibition imbalance in neural networks is widely linked to neurological and neuropsychiatric disorders. However, how genetic factors alter neuronal activity, leading to excitation-inhibition imbalance, remains unclear. Here, using the C. elegans locomotor circuit, we examine how altering neuronal activity for varying time periods affects synaptic release pattern and animal behavior. We show that while short-duration activation of excitatory cholinergic neurons elicits a reversible enhancement of presynaptic strength, persistent activation results to asynchronous and reduced cholinergic drive, inducing imbalance between endogenous excitation and inhibition. We find that the neuronal calcium sensor protein NCS-2 is required for asynchronous cholinergic release in an activity-dependent manner and dampens excitability of inhibitory neurons non-cell autonomously. The function of NCS-2 requires its Ca2+ binding and membrane association domains. These results reveal a synaptic mechanism implicating asynchronous release in regulation of excitation-inhibition balance.
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Project description:Neuropeptides are secreted molecules that have conserved roles modulating many processes, including mood, reproduction, and feeding. Dysregulation of neuropeptide signaling is also implicated in neurological disorders such as epilepsy. However, much is unknown about the mechanisms regulating specific neuropeptides to mediate behavior. Here, we report that the expression levels of dozens of neuropeptides are up-regulated in response to circuit activity imbalance in C. elegans. acr-2 encodes a homolog of human nicotinic receptors, and functions in the cholinergic motoneurons. A hyperactive mutation, acr-2(gf), causes an activity imbalance in the motor circuit. We performed cell-type specific transcriptomic analysis and identified genes differentially expressed in acr-2(gf), compared to wild type. The most over-represented class of genes are neuropeptides, with insulin-like-peptides (ILPs) the most affected. Moreover, up-regulation of neuropeptides occurs in motoneurons, as well as sensory neurons. In particular, the induced expression of the ILP ins-29 occurs in the BAG neurons, which were previously shown to function in gas-sensing. We also show that this up-regulation of ins-29 in acr-2(gf) animals is activity-dependent. Our genetic and molecular analyses support cooperative effects for ILPs and other neuropeptides in promoting motor circuit activity in the acr-2(gf) background. Together, this data reveals that a major transcriptional response to motor circuit dysregulation is in up-regulation of multiple neuropeptides, and suggests that BAG sensory neurons can respond to intrinsic activity states to feedback on the motor circuit.
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Project description:A loss of the excitation/inhibition (E/I) balance in the neural circuit has emerged as a common neuropathological feature in many neurodevelopmental disorders. Rett syndrome (RTT), a prevalent neurodevelopmental disorder that affects 1:10,000-15,000 women globally, is caused by loss-of-function mutations in the Methyl-CpG-binding Protein-2 (Mecp2) gene. E/I imbalance is recognized as the leading cellular and synaptic hallmark that is fundamental to diverse RTT neurological symptoms, including stereotypic hand movements, impaired motor coordination, breathing irregularities, seizures, and learning/memory dysfunctions. E/I balance in RTT is not homogeneously altered but demonstrates brain region and cell type specificity instead. In this review, I elaborate on the current understanding of the loss of E/I balance in a range of brain areas at molecular and cellular levels. I further describe how the underlying cellular mechanisms contribute to the disturbance of the proper E/I ratio. Last, I discuss current pharmacologic innervations for RTT and their role in modifying the E/I balance.
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Project description:Understanding the relationship between external stimuli and the spiking activity of cortical populations is a central problem in neuroscience. Dense recurrent connectivity in local cortical circuits can lead to counterintuitive response properties, raising the question of whether there are simple arithmetical rules for relating circuits' connectivity structure to their response properties. One such arithmetic is provided by the mean field theory of balanced networks, which is derived in a limit where excitatory and inhibitory synaptic currents precisely balance on average. However, balanced network theory is not applicable to some biologically relevant connectivity structures. We show that cortical circuits with such structure are susceptible to an amplification mechanism arising when excitatory-inhibitory balance is broken at the level of local subpopulations, but maintained at a global level. This amplification, which can be quantified by a linear correction to the classical mean field theory of balanced networks, explains several response properties observed in cortical recordings and provides fundamental insights into the relationship between connectivity structure and neural responses in cortical circuits.
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Project description:Neuropeptides are secreted molecules that have conserved roles modulating many processes, including mood, reproduction, and feeding. Dysregulation of neuropeptide signaling is also implicated in neurological disorders such as epilepsy. However, much is unknown about the mechanisms regulating specific neuropeptides to mediate behavior. Here, we report that the expression levels of dozens of neuropeptides are up-regulated in response to circuit activity imbalance in C. elegans. acr-2 encodes a homolog of human nicotinic receptors, and functions in the cholinergic motoneurons. A hyperactive mutation, acr-2(gf), causes an activity imbalance in the motor circuit. We performed cell-type specific transcriptomic analysis and identified genes differentially expressed in acr-2(gf), compared to wild type. The most over-represented class of genes are neuropeptides, with insulin-like-peptides (ILPs) the most affected. Moreover, up-regulation of neuropeptides occurs in motor neurons, as well as sensory neurons. In particular, the induced expression of the ILP ins-29 occurs in the BAG neurons, which are previously shown to function in gas-sensing. We also show that this up-regulation of ins-29 in acr-2(gf) animals is activity-dependent. Our genetic and molecular analyses support cooperative effects for ILPs and other neuropeptides in promoting motor circuit activity in the acr-2(gf) background. Together, this data reveals that a major transcriptional response to motor circuit dysregulation is in up-regulation of multiple neuropeptides, and suggests that BAG sensory neurons can respond to intrinsic activity states to feedback on the motor circuit.
2019-10-22 | GSE139212 | GEO
Project description:Possessing the ability to noninvasively elicit brain circuit activity yields immense experimental and therapeutic power. Most currently employed neurostimulation methods rely on the somewhat invasive use of stimulating electrodes or photon-emitting devices. Due to its ability to noninvasively propagate through bone and other tissues in a focused manner, the implementation of ultrasound (US) represents a compelling alternative approach to current neuromodulation strategies. Here, we investigated the influence of low-intensity, low-frequency ultrasound (LILFU) on neuronal activity. By transmitting US waveforms through hippocampal slice cultures and ex vivo mouse brains, we determined LILFU is capable of remotely and noninvasively exciting neurons and network activity. Our results illustrate that LILFU can stimulate electrical activity in neurons by activating voltage-gated sodium channels, as well as voltage-gated calcium channels. The LILFU-induced changes in neuronal activity were sufficient to trigger SNARE-mediated exocytosis and synaptic transmission in hippocampal circuits. Because LILFU can stimulate electrical activity and calcium signaling in neurons as well as central synaptic transmission we conclude US provides a powerful tool for remotely modulating brain circuit activity.
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Project description:BackgroundExcitation/inhibition imbalance (E/I imbalance), which involves an increase of alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptors (AMPARs) and decrease of gamma-aminobutyric acid type A (GABA) type A receptors (GABAaRs) on the neuron surface, has been documented in the pathogenesis of seizures. Notably, it has been established that both the glutamate receptor subunit 2 (GluR2) of AMPARs and beta 2/3 subunits of GABAaRs (Gabrb2+3) participate in the recycling mechanism mediated by the kinesin heavy chain isoform 5A (KIF5A), which determines the number of neuron surface receptors. However, it remains unclear whether receptor recycling is involved in the pathogenesis of seizures.MethodsTwelve adult male Sprague-Dawley rats were randomly allocated to the normal control (Ctl) group (n=6) and the pentylenetetrazol (PTZ)-induced seizure (Sez) group (n=6). The rats in the Ctl group were treated with saline. The rats in the Sez group received an intraperitoneal injection of PTZ at an initial dose of 40 mg/kg. Primary cultured neurons were obtained from newborn rats (24-hour-old). The neurons were exposed to magnesium-free (Mg2+-free) extracellular fluid for 3 hours to establish the seizure model in vitro. We detected the electrophysiology of the seizure model, the expression levels of KIF5A, GluR2, and Gabrb2+3, the recycling ratio of GluR2 and Gabrb2+3, the interaction between KIF5A and GluR2, and the interaction between KIF5A and Gabrb2+3.ResultsIn the Sez group, the expression of GluR2 on the cell surface was increased and the expression of Gabrb2+3 on the cell surface was decreased. The amplitude and frequency of action potentials were significantly increased in the Mg2+-free group. The amplitude and decay time of AMPAR-mediated miniature excitatory postsynaptic currents were increased in the Mg2+-free group. The amplitude and decay time of miniature inhibitory postsynaptic currents were decreased in the Mg2+-free group. The recycling ratio of GluR2 was increased and the recycling ratio of Gabrb2+3 was decreased in the Mg2+-free group. The interaction between KIF5A and GluR2 was increased, and the interaction between KIF5A and Gabrb2+3 was decreased in the seizure model in vivo and in vitro.ConclusionsThe recycling of AMPA receptors/GABAa receptors is related to E/I imbalance and may be regulated by KIF5A.
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Project description:Autism spectrum disorder (ASD) currently affects 1 in 59 children, although the aetiology of this disorder remains unknown. Faced with multiple seemingly disparate and noncontiguous neurobiological alterations, Rubenstein and Merzenich hypothesized that imbalances between excitatory and inhibitory neurosignaling (E/I imbalance) underlie ASD. Since this initial statement, there has been a major focus examining this exact topic spanning both clinical and preclinical realms. The purpose of this article is to review the clinical neuroimaging literature surrounding E/I imbalance as an aetiology of ASD. Evidence for E/I imbalance is presented from several complementary clinical techniques including magnetic resonance spectroscopy, magnetoencephalography and transcranial magnetic stimulation. Additionally, two GABAergic potential interventions for ASD, which explicitly attempt to remediate E/I imbalance, are reviewed. The current literature suggests E/I imbalance as a useful framework for discussing the neurobiological etiology of ASD in at least a subset of affected individuals. While not constituting a completely unifying aetiology, E/I imbalance may be relevant as one of several underlying neuropathophysiologies that differentially affect individuals with ASD. Such statements do not diminish the value of the E/I imbalance concept-instead they suggest a possible role for the characterization of E/I imbalance, as well as other underlying neuropathophysiologies, in the biologically-based subtyping of individuals with ASD for potential applications including clinical trial enrichment as well as treatment triage.
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Project description:Autism is characterized by disruption in multiple dimensions of perception, emotion, language and social cognition. Many hypotheses for the underlying neurophysiological basis have been proposed. Among these is the excitation/inhibition (E/I) imbalance hypothesis, which states that levels of cortical excitation and inhibition are disrupted in autism. We tested this theory in the visual system, because vision is one of the better understood systems in neuroscience, and because the E/I imbalance theory has been proposed to explain hypersensitivity to sensory stimuli in autism. We conducted two experiments on binocular rivalry, a well-studied psychophysical phenomenon that depends critically on excitation and inhibition levels in cortex. Using a computational model, we made specific predictions about how imbalances in excitation and inhibition levels would affect perception during two aspects of binocular rivalry: mixed perception (Experiment 1) and traveling waves (Experiment 2). We found no significant differences in either of these phenomena between high-functioning adults with autism and controls, and no evidence for a relationship between these measurements and the severity of autism. These results do not conclusively rule out an excitation/inhibition imbalance in the visual system of those with autism, but they suggest that such an imbalance, if it exists, is likely to be small in magnitude.
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