Excitation-inhibition Balance Research Articles

Inhibitory subpopulations in preBötzinger Complex play distinct roles in modulating inspiratory rhythm and pattern.

Inhibitory neurons embedded within mammalian neural circuits shape breathing, walking, and other rhythmic motor behaviors. At the core of the neural circuit controlling breathing is the preBötzinger Complex (preBötC), where GABAergic (GAD1/2+) and glycinergic (GlyT2+) neurons are functionally and anatomically intercalated among glutamatergic Dbx1-derived (Dbx1+) neurons that generate rhythmic inspiratory drive. The roles of these preBötC inhibitory neurons in breathing remain unclear. We first characterized the spatial distribution of molecularly-defined preBötC inhibitory subpopulations in male and female neonatal double reporter mice expressing either tdTomato or EGFP in GlyT2+, GAD1+, or GAD2+ neurons. We found that the majority of preBötC inhibitory neurons expressed both GlyT2 and GAD2 while a much smaller subpopulation also expressed GAD1. To determine the functional role of these subpopulations, we used holographic photostimulation, a patterned illumination technique, in rhythmically active medullary slices from neonatal Dbx1tdTomato;GlyT2EGFP and Dbx1tdTomato;GAD1EGFP double reporter mice of either sex. Stimulation of 4 or 8 preBötC GlyT2+ neurons during endogenous rhythm prolonged the interburst interval in a phase-dependent manner and increased the latency to burst initiation when bursts were evoked by stimulation of Dbx1+ neurons. In contrast, stimulation of 4 or 8 preBötC GAD1+ neurons did not affect interburst interval or latency to burst initiation. Instead, photoactivation of GAD1+ neurons during the inspiratory burst prolonged endogenous and evoked burst duration and decreased evoked burst amplitude. We conclude that GlyT2+/GAD2+ neurons modulate breathing rhythm by delaying burst initiation while a smaller GAD1+ subpopulation shapes inspiratory patterning by altering burst duration and amplitude.Significance Statement Inhibition is critical for control of rhythmic motor behaviors, such as breathing, walking, and chewing. We reveal functional differences among embedded preBötC inhibitory micro-cir-cuits that contribute to excitation-inhibition balance governing distinct processes in the breathing motor program. We develop approaches for high throughput analysis of spatial distributions of neurons in tissue and for dynamic functional manipulations via an important extension of holographic photostimulation to sequences of patterns that more closely mimics physiological neural activity. Our study challenges the current understanding of the role of inhibition in breathing and provides novel insights into specific roles of inhibitory neurons in neural circuits controlling breathing that are applicable to other rhythmic motor behaviors in health and disease.

Hippocampal excitation-inhibition balance underlies the 5-HT2C receptor in modulating depressive behaviours.

The implication of 5-hydroxytryptamine 2C receptor (5-HT2CR) in depression is a topic of debate, and the underlying mechanisms remain largely unclear. We now elucidate hippocampal excitation-inhibition (E/I) balance underlies the regulatory effects of 5-HT2CR in depression. Molecular biological analyses showed that chronic mild stress (CMS) reduced the expression of 5-HT2CR in hippocampus. We revealed that inhibition of 5-HT2CR induced depressive-like behaviors, reduced GABA release and shifted the E/I balance towards excitation in CA3 pyramidal neurons by using behavioral analyses, microdialysis coupled with mass spectrum, and electrophysiological recording. Moreover, 5-HT2CR modulated neuronal nitric oxide synthase (nNOS)-carboxy-terminal PDZ ligand of nNOS (CAPON) interaction through influencing intracellular Ca2+ release, as determined by fiber photometry and coimmunoprecipitation. Notably, disruption of nNOS-CAPON by specific small molecule compound ZLc-002 or AAV-CMV-CAPON-125C-GFP, abolished 5-HT2CR inhibition-induced depressive-like behaviors, as well as the impairment in soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly-mediated GABA vesicle release and a consequent E/I imbalance. Importantly, optogenetic inhibition of CA3 GABAergic neurons prevented the effects of AAV-CMV-CAPON-125C-GFP on depressive behaviors in the presence of 5-HT2CR antagonist. Conclusively, our findings disclose the regulatory role of 5-HT2CR in depressive-like behaviors and highlight the hippocampal nNOS-CAPON coupling-triggered E/I imbalance as a pivotal cellular event underpinning the behavioral consequences of 5-HT2CR inhibition.

Assessment of the excitation-inhibition ratio in the Fmr1 KO2 mouse using neuronal oscillation dynamics.

In vitro and ex vivo studies have shown consistent indications of hyperexcitability in the Fragile X Messenger Ribonucleoprotein 1 (Fmr1) knockout mouse model of autism spectrum disorder. We recently introduced a method to quantify network-level functional excitation-inhibition ratio from the neuronal oscillations. Here, we used this measure to study whether the implicated synaptic excitation-inhibition disturbances translate to disturbances in network physiology in the Fragile X Messenger Ribonucleoprotein 1 (Fmr1) gene knockout model. Vigilance-state scoring was used to extract segments of inactive wakefulness as an equivalent behavioral condition to the human resting-state and, subsequently, we performed high-frequency resolution analysis of the functional excitation-inhibition biomarker, long-range temporal correlations, and spectral power. We corroborated earlier studies showing increased high-frequency power in Fragile X Messenger Ribonucleoprotein 1 (Fmr1) knockout mice. Long-range temporal correlations were higher in the gamma frequency ranges. Contrary to expectations, functional excitation-inhibition was lower in the knockout mice in high frequency ranges, suggesting more inhibition-dominated networks. Exposure to the Gamma-aminobutyric acid (GABA)-agonist clonazepam decreased the functional excitation-inhibition in both genotypes, confirming that increasing inhibitory tone results in a reduction of functional excitation-inhibition. In addition, clonazepam decreased electroencephalogram power and increased long-range temporal correlations in both genotypes. These findings show applicability of these new resting-state electroencephalogram biomarkers to animal for translational studies and allow investigation of the effects of lower-level disturbances in excitation-inhibition balance.

Clinical, behavioral, and electrophysiological profiles along a continuum of suicide risk: evidence from an implicit association task.

An urgent need exists to identify neural correlates associated with differing levels of suicide risk and develop novel, rapid-acting therapeutics to modulate activity within these neural networks. Electrophysiological correlates of suicide were evaluated using magnetoencephalography (MEG) in 75 adults with differing levels of suicide risk. During MEG scanning, participants completed a modified Life-Death Implicit Association Task. MEG data were source-localized in the gamma (30-58 Hz) frequency, a proxy measure of excitation-inhibition balance. Dynamic causal modeling was used to evaluate differences in connectivity estimates between risk groups. A proof-of-concept, open-label, pilot study of five high risk participants examined changes in gamma power after administration of ketamine (0.5 mg/kg), an NMDAR antagonist with rapid anti-suicide ideation effects. Implicit self-associations with death were stronger in the highest suicide risk group relative to all other groups, which did not differ from each other. Higher gamma power for self-death compared to self-life associations was found in the orbitofrontal cortex for the highest risk group and the insula and posterior cingulate cortex for the lowest risk group. Connectivity estimates between these regions differentiated the highest risk group from the full sample. Implicit associations with death were not affected by ketamine, but enhanced gamma power was found for self-death associations in the left insula post-ketamine compared to baseline. Differential implicit cognitive processing of life and death appears to be linked to suicide risk, highlighting the need for objective measures of suicidal states. Pharmacotherapies that modulate gamma activity, particularly in the insula, may help mitigate risk.Clinicaltrials.gov identifier: NCT02543983, NCT00397111.

Bionic Olfactory Synaptic Transistors for Artificial Neuromotor Pathway Construction and Gas Recognition

AbstractThe superior recognition ability and excitatory–inhibitory balance of the olfactory system has important applications in the efficient recognition, analysis, and processing of data. In this study, transistor synaptic devices are prepared utilizing poly‐diketo‐pyrrolopyrrole‐selenophene polymer (PTDPPSe‐5Si) with excellent electrical properties as the active layer, and dual‐gas pulses are applied for the first time to simulate excitatory and inhibitory behaviors in the olfactory system. Basic synaptic properties are successfully simulated, such as excitatory/inhibitory postsynaptic currents (EPSC/IPSC), and long‐term potentiation/depression (LTP/LTD). The regulation of excitatory–inhibitory balance in biomimetic olfaction is successfully simulated. This working mechanism is attributed to the capture and release of carriers in the channel induced by the gas's electron‐donating and electron‐withdrawing characteristics. The neuromotor pathway is constructed using synaptic devices as the key processing unit, which enables the integration of information from neurons and the output of information from motor neurons. A convolutional neural network is constructed to achieve recognition of eight common laboratory gas types and concentrations with a recognition accuracy of over 97%. The simulated excitatory and inhibitory behaviors exhibited by this device hold significant importance for the development of artificial neural networks, intelligent frameworks, and neural robots.

Control of neuronal excitation-inhibition balance by BMP-SMAD1 signalling.

Throughout life, neuronal networks in the mammalian neocortex maintain a balance of excitation and inhibition, which is essential for neuronal computation1,2. Deviations from a balanced state have been linked to neurodevelopmental disorders, and severe disruptions result in epilepsy3-5. To maintain balance, neuronal microcircuits composed of excitatory and inhibitory neurons sense alterations in neural activity and adjust neuronal connectivity and function. Here we identify a signalling pathway in the adult mouse neocortex that is activated in response to increased neuronal network activity. Overactivation of excitatory neurons is signalled to the network through an increase in the levels of BMP2, a growth factor that is well known for its role as a morphogen in embryonic development. BMP2 acts on parvalbumin-expressing (PV) interneurons through the transcription factor SMAD1, which controls an array of glutamatergic synapse proteins and components of perineuronal nets. PV-interneuron-specific disruption of BMP2-SMAD1 signalling is accompanied by a loss of glutamatergic innervation in PV cells, underdeveloped perineuronal nets and decreased excitability. Ultimately, this impairment of the functional recruitment of PV interneurons disrupts the cortical excitation-inhibition balance, with mice exhibiting spontaneous epileptic seizures. Our findings suggest that developmental morphogen signalling is repurposed to stabilize cortical networks in the adult mammalian brain.

Erythropoietin restrains the inhibitory potential of interneurons in the mouse hippocampus.

Severe psychiatric illnesses, for instance schizophrenia, and affective diseases or autism spectrum disorders, have been associated with cognitive impairment and perturbed excitatory-inhibitory balance in the brain. Effects in juvenile mice can elucidate how erythropoietin (EPO) might aid in rectifying hippocampal transcriptional networks and synaptic structures of pyramidal lineages, conceivably explaining mitigation of neuropsychiatric diseases. An imminent conundrum is how EPO restores synapses by involving interneurons. By analyzing ~12,000 single-nuclei transcriptomic data, we generated a comprehensive molecular atlas of hippocampal interneurons, resolved into 15 interneuron subtypes. Next, we studied molecular alterations upon recombinant human (rh)EPO and saw that gene expression changes relate to synaptic structure, trans-synaptic signaling and intracellular catabolic pathways. Putative ligand-receptor interactions between pyramidal and inhibitory neurons, regulating synaptogenesis, are altered upon rhEPO. An array of in/ex vivo experiments confirms that specific interneuronal populations exhibit reduced dendritic complexity, synaptic connectivity, and changes in plasticity-related molecules. Metabolism and inhibitory potential of interneuron subgroups are compromised, leading to greater excitability of pyramidal neurons. To conclude, improvement by rhEPO of neuropsychiatric phenotypes may partly owe to restrictive control over interneurons, facilitating re-connectivity and synapse development.

Parvalbumin interneuron deficiency in the prefrontal and motor cortices of spontaneously hypertensive rats: an attention-deficit hyperactivity disorder animal model insight.

Attention deficit hyperactivity disorder (ADHD) is characterized by impairments in developmental-behavioral inhibition, resulting in impulsivity and hyperactivity. Recent research has underscored cortical inhibition deficiencies in ADHD via the gamma-aminobutyric acid (GABA)ergic system, which is crucial for maintaining excitatory-inhibitory balance in the brain. This study explored postnatal changes in parvalbumin (PV) immunoreactivity, indicating GABAergic interneuron types, in the prefrontal (PFC) and motor (MC) cortices of spontaneously hypertensive rats (SHRs), an ADHD animal model. Examining PV- positive (PV+) cells associated with dopamine D2 receptors (D2) and the impact of dopamine on GABA synthesis, we also investigated changes in the immunoreactivity of D2 and tyrosine hydroxylase (TH). Brain sections from 4- to 10-week-old SHRs and Wistar Kyoto rats (WKYs) were immunohistochemically analyzed, comparing PV+, D2+ cells, and TH+ fiber densities across age-matched SHRs and WKYs in specific PFC/MC regions. The results revealed significantly reduced PV+ cell density in SHRs: prelimbic (~20% less), anterior cingulate (~15% less), primary (~15% less), and secondary motor (~17% less) cortices. PV+ deficits coincided with the upregulation of D2 in prepubertal SHRs and the downregulation of TH predominantly in pubertal/postpubertal SHRs. Reduced PV+ cells in various PFC regions could contribute to inattention/behavioral alterations in ADHD, while MC deficits could manifest as motor hyperactivity. D2 upregulation and TH deficits may impact GABA synthesis, exacerbating behavioral deficits in ADHD. These findings not only shed new light on ADHD pathophysiology but also pave the way for future research endeavors.

Sleep deprivation drives brain-wide changes in cholinergic presynapse abundance in Drosophila melanogaster

Sleep is an evolutionarily conserved state that supports brain functions, including synaptic plasticity, in species across the animal kingdom. Here, we examine the neuroanatomical and cell-type distribution of presynaptic scaling in the fly brain after sleep loss. We previously found that sleep loss drives accumulation of the active zone scaffolding protein Bruchpilot (BRP) within cholinergic Kenyon cells of the Drosophila melanogaster mushroom body (MB), but not in other classes of MB neurons. To test whether similar cell type-specific trends in plasticity occur broadly across the brain, we used a flp-based genetic reporter to label presynaptic BRP in cholinergic, dopaminergic, GABAergic, or glutamatergic neurons. We then collected whole-brain confocal image stacks of BRP intensity to systematically quantify BRP, a marker of presynapse abundance, across 37 neuropil regions of the central fly brain. Our results indicate that sleep loss, either by overnight (12-h) mechanical stimulation or chronic sleep disruption in insomniac mutants, broadly elevates cholinergic synapse abundance across the brain, while synapse abundance in neurons that produce other neurotransmitters undergoes weaker, if any, changes. Extending sleep deprivation to 24 h drives brain-wide upscaling in glutamatergic, but not other, synapses. Finally, overnight male-male social pairings induce increased BRP in excitatory synapses despite male-female pairings eliciting more waking activity, suggesting experience-specific plasticity. Within neurotransmitter class and waking context, BRP changes are similar across the 37 neuropil domains, indicating that similar synaptic scaling rules may apply across the brain during acute sleep loss and that sleep need may broadly alter excitatory-inhibitory balance in the central brain.

The connectivity degree controls the difficulty in reservoir design of random boolean networks.

Reservoir Computing (RC) is a paradigm in artificial intelligence where a recurrent neural network (RNN) is used to process temporal data, leveraging the inherent dynamical properties of the reservoir to perform complex computations. In the realm of RC, the excitatory-inhibitory balance b has been shown to be pivotal for driving the dynamics and performance of Echo State Networks (ESN) and, more recently, Random Boolean Network (RBN). However, the relationship between b and other parameters of the network is still poorly understood. This article explores how the interplay of the balance b, the connectivity degree K (i.e., the number of synapses per neuron) and the size of the network (i.e., the number of neurons N) influences the dynamics and performance (memory and prediction) of an RBN reservoir. Our findings reveal that K and b are strongly tied in optimal reservoirs. Reservoirs with high K have two optimal balances, one for globally inhibitory networks (b < 0), and the other one for excitatory networks (b > 0). Both show asymmetric performances about a zero balance. In contrast, for moderate K, the optimal value being K = 4, best reservoirs are obtained when excitation and inhibition almost, but not exactly, balance each other. For almost all K, the influence of the size is such that increasing N leads to better performance, even with very large values of N. Our investigation provides clear directions to generate optimal reservoirs or reservoirs with constraints on size or connectivity.

Shift in excitation-inhibition balance underlies perceptual learning of temporal discrimination

Temporal perceptual learning (TPL) constitutes a unique and profound demonstration of neural plasticity within the brain. Our understanding for the neurometabolic changes associated with TPL on the other hand has been limited in part by the use of traditional fMRI approaches. Since plasticity in the visual cortex has been shown to underlie perceptual learning of visual information, we tested the hypothesis that TPL of an auditory interval involves a similar change in plasticity of the auditory pathway and if so, whether these changes take place in a lower-order sensory-specific brain area such as the primary auditory cortex (A1), or a higher-order modality-independent brain area such as the inferior parietal cortex (IPC). This distinction will inform us of the mechanisms underlying perceptual learning as well as the locus of change as it relates to TPL. In the present study, we took advantage of a new technique: proton magnetic resonance spectroscopy (MRS) in combination with psychophysical measures to provide the first evidence of changes in neurometabolic processing following 5 days of temporal discrimination training. We measured the (E)xcitation-to-(I)nhibition ratio as an index of learning in the right IPC and left A1 while participants learned an auditory two-tone discrimination task. During the first day of training, we found a significant task-related increase in functional E/I ratio within the IPC. While the A1 exhibited the opposite pattern of neurochemical activity, this relationship did not reach statistical significance. After timing performance has reached a plateau, there were no further changes to functional E/I. These findings support the hypothesis that improvements in temporal discrimination relies on neuroplastic changes in the IPC, but it is possible that both areas work synergistically to acquire a temporal interval.

Intersectional strategy to study cortical inhibitory parvalbumin-expressing interneurons

Parvalbumin-expressing (PV) interneurons are key neuronal elements to a global excitatory-inhibitory balance in normal cortical functioning. To better understand the circuit functions of PV interneurons, reliable animal models are needed. This study investigated the sensitivity and specificity of the most frequently used PV-Cre/tdTomato mouse line in this regard. The colocalization of the transgene (tdTomato) with the parvalbumin protein, with GAD1 (a conclusive inhibitory cell marker) and Vglut1 (a conclusive excitatory cell marker) as well as with a marker for perineuronal nets (WFA) was assessed and a substantial proportion of layer 5 PV neurons was found to be excitatory and not inhibitory in the PV-Cre/tdTomato mouse. The intersectional transgenic mouse line Vgat-Cre/PV-Flp/tdTomato provided a solution, since no colocalization of tdTomato with the Vglut1 probe was found there. In conclusion, the Vgat-Cre/PV-Flp/tdTomato mouse line seems to be a more reliable animal model for functional studies of GABAergic PV interneurons.

Excitation-Inhibition Balance, Neural Criticality, and Activities in Neuronal Circuits.

Neural activities in local circuits exhibit complex and multilevel dynamic features. Individual neurons spike irregularly, which is believed to originate from receiving balanced amounts of excitatory and inhibitory inputs, known as the excitation-inhibition balance. The spatial-temporal cascades of clustered neuronal spikes occur in variable sizes and durations, manifested as neural avalanches with scale-free features. These may be explained by the neural criticality hypothesis, which posits that neural systems operate around the transition between distinct dynamic states. Here, we summarize the experimental evidence for and the underlying theory of excitation-inhibition balance and neural criticality. Furthermore, we review recent studies of excitatory-inhibitory networks with synaptic kinetics as a simple solution to reconcile these two apparently distinct theories in a single circuit model. This provides a more unified understanding of multilevel neural activities in local circuits, from spontaneous to stimulus-response dynamics.

Multipollutant reciprocal neurological hazard from smoke particulate matter and heavy metals cadmium and lead in brain nerve terminals

Heavy metals, Cd2+ and Pb2+, and carbonaceous air pollution particulate matter are hazardous neurotoxicants. Here, a capability of water-suspended smoke particulate matter preparations obtained from poplar wood (WPs) and polypropylene fibers (medical facemasks) (MPs) to influence Cd2+/Pb2+-induced neurotoxicity, and vice versa, was monitored using biological system, i.e. isolated presynaptic rat cortex nerve terminals. Combined application of Pb2+ and WPs/MPs to nerve terminals in an acute manner revealed that smoke preparations did not change a Pb2+-induced increase in the extracellular levels of excitatory neurotransmitter L-[14C]glutamate and inhibitory one [3H]GABA, thereby demonstrating additive result and no interference of neurotoxic effects of Pb2+ and particulate matter. Whereas, both smoke preparations decreased a Cd2+-induced increase in the extracellular level of L-[14C]glutamate and [3H]GABA in nerve terminals. In fluorimetric measurements, the metals and smoke preparations demonstrated additive effects on the membrane potential of nerve terminals causing membrane depolarisation. WPs/MPs-induced reduction of spontaneous ROS generation was mitigated by Cd2+ and Pb2+. Therefore, a potential variety of multipollutant heavy metal-/airborne particulate-induced effects on key presynaptic processes was revealed. Multipollutant reciprocal neurological hazard through disturbance of the excitation-inhibition balance, membrane potential and ROS generation was evidenced. This multipollutant approach and data contribute to up-to-date environmental quality/health risk estimation.

GABAergic inhibition shapes behavior and neural dynamics in human visual working memory.

Neuronal inhibition, primarily mediated by GABAergic neurotransmission, is crucial for brain development and healthy cognition. Gamma-aminobutyric acid concentration levels in sensory areas have been shown to correlate with hemodynamic and oscillatory neuronal responses. How these measures relate to one another during working memory, a higher-order cognitive process, is still poorly understood. We address this gap by collecting magnetoencephalography, functional magnetic resonance imaging, and Flumazenil positron emission tomography data within the same subject cohort using an n-back working-memory paradigm. By probing the relationship between GABAA receptor distribution, neural oscillations, and Blood Oxygen Level Dependent (BOLD) modulations, we found that GABAA receptor density in higher-order cortical areas predicted the reaction times on the working-memory task and correlated positively with the peak frequency of gamma power modulations and negatively with BOLD amplitude. These findings support and extend theories linking gamma oscillations and hemodynamic responses to gamma-aminobutyric acid neurotransmission and to the excitation-inhibition balance and cognitive performance in humans. Considering the small sample size of the study, future studies should test whether these findings also hold for other, larger cohorts as well as to examine in detail how the GABAergic system and neural fluctuations jointly support working-memory task performance.

Synaptic Facilitation: A Key Biological Mechanism for Resource Allocation in Computational Models of Working Memory

Working memory (WM) is a crucial cognitive function required to maintain and manipulate information that is no longer present through the senses. Two key features of WM are its limited capacity and the emergence of serial order effects. This study investigates how synaptic facilitation and diverse display dynamics influence the encoding and retention of multiple items in WM. A biophysically inspired attractor model of WM, endowed with synaptic facilitation, is considered in this study. The investigation delves into the behaviour of the model under both sequential and simultaneous display protocols. Synaptic facilitation plays a crucial role in establishing the response of the WM system by regulating resource allocation during the encoding stage. It boosts WM capacity and is a key mechanism in the emergence of serial order effects. The synaptic facilitation time constant (τF\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\ au _F$$\\end{document}) is critical in modulating these effects, and its heterogeneity in the prefrontal cortex (PFC) may contribute to the combination of primacy and recency effects observed experimentally. Additionally, we demonstrate that the WM capacity exhibited by the network is heavily influenced by factors such as the stimuli nature, and their display duration. Although the network connectivity determines the WM capacity by regulating the excitation-inhibition balance, the display protocol modulates its effective limit. Our findings shed light on how different stimulation protocol dynamics affect WM, underscoring the importance of synaptic facilitation and experimental protocol design in modulating WM capacity.

TAAR1 agonist ulotaront modulates striatal and hippocampal glutamate function in a state-dependent manner

Aberrant dopaminergic and glutamatergic function, particularly within the striatum and hippocampus, has repeatedly been associated with the pathophysiology of schizophrenia. Supported by preclinical and recent clinical data, trace amine-associated receptor 1 (TAAR1) agonism has emerged as a potential new treatment approach for schizophrenia. While current evidence implicates TAAR1-mediated regulation of dopaminergic tone as the primary circuit mechanism, little is known about the effects of TAAR1 agonists on the glutamatergic system and excitation-inhibition balance. Here we assessed the impact of ulotaront (SEP-363856), a TAAR1 agonist in Phase III clinical development for schizophrenia, on glutamate function in the mouse striatum and hippocampus. Ulotaront reduced spontaneous glutamatergic synaptic transmission and neuronal firing in striatal and hippocampal brain slices, respectively. Interestingly, ulotaront potentiated electrically-evoked excitatory synaptic transmission in both brain regions, suggesting the ability to modulate glutamatergic signaling in a state-dependent manner. Similar striatal effects were also observed with the TAAR1 agonist, RO5166017. Furthermore, we show that ulotaront regulates excitation-inhibition balance in the striatum by specifically modulating glutamatergic, but not GABAergic, spontaneous synaptic events. These findings expand the mechanistic circuit hypothesis of ulotaront and TAAR1 agonists, which may be uniquely positioned to normalize both the excessive dopaminergic tone and regulate abnormal glutamatergic function associated with schizophrenia.

A data assimilation method to track excitation-inhibition balance change using scalp EEG

Recent neuroscience studies have suggested that controlling the excitation and inhibition (E/I) balance is essential for maintaining normal brain function. However, while control of time-varying E/I balance is considered essential for perceptual and motor learning, an efficient method for estimating E/I balance changes has yet to be established. To tackle this issue, we propose a method to estimate E/I balance changes by applying neural-mass model-based tracking of the brain state using the Ensemble Kalman Filter. In this method, the parameters of synaptic E/I gains in the model are estimated from observed electroencephalography signals. Moreover, the index of E/I balance was defined by calculating the ratio between synaptic E/I gains based on estimated parameters. The method was validated by showing that it could estimate E/I balance changes from human electroencephalography data at the sub-second scale, indicating that it has the potential to quantify how time-varying changes in E/I balance influence changes in perceptual and motor learning. Furthermore, this method could be used to develop an E/I balance-based neurofeedback training method for clinical use.

Astrocyte chloride, excitatory-inhibitory balance and epilepsy.

Astrocyte chloride, excitatory-inhibitory balance and epilepsy.

Serine 937 phosphorylation enhances KCC2 activity and strengthens synaptic inhibition

The potassium chloride cotransporter KCC2 is crucial for Cl- extrusion from mature neurons and thus key to hyperpolarizing inhibition. Auditory brainstem circuits contain well-understood inhibitory projections and provide a potent model to study the regulation of synaptic inhibition. Two peculiarities of the auditory brainstem are (i) posttranslational activation of KCC2 during development and (ii) extremely negative reversal potentials in specific circuits. To investigate the role of the potent phospho-site serine 937 therein, we generated a KCC2 Thr934Ala/Ser937Asp double mutation, in which Ser937 is replaced by aspartate mimicking the phosphorylated state, and the neighbouring Thr934 arrested in the dephosphorylated state. This double mutant showed a twofold increased transport activity in HEK293 cells, raising the hypothesis that auditory brainstem neurons show lower [Cl−]i. and increased glycinergic inhibition. This was tested in a mouse model carrying the same KCC2 Thr934Ala/Ser937Asp mutation by the use of the CRISPR/Cas9 technology. Homozygous KCC2 Thr934Ala/Ser937Asp mice showed an earlier developmental onset of hyperpolarisation in the auditory brainstem. Mature neurons displayed stronger glycinergic inhibition due to hyperpolarized ECl−. These data demonstrate that phospho-regulation of KCC2 Ser937 is a potent way to interfere with the excitation-inhibition balance in neural circuits.