A Reduction in the Readily Releasable Vesicle Pool Impairs GABAergic Inhibition in the Hippocampus after Blood-Brain Barrier Dysfunction.

Major burdens for patients suffering from stroke are cognitive co-morbidities and epileptogenesis. Neural network disinhibition and deficient inhibitive pulses for fast network activities may result from impaired presynaptic release of the inhibitory neurotransmitter GABA. To test this hypothesis, a cortical photothrombotic stroke was induced in Sprague Dawley rats, and inhibitory currents were recorded seven days later in the peri-infarct blood-brain barrier disrupted (BBBd) hippocampus via patch-clamp electrophysiology in CA1 pyramidal cells (PC). Miniature inhibitory postsynaptic current (mIPSC) frequency was reduced to about half, and mIPSCs decayed faster in the BBBd hippocampus. Furthermore, the paired-pulse ratio of evoked GABA release was increased at 100 Hz, and train stimulations with 100 Hz revealed that the readily releasable pool (RRP), usually assumed to correspond to the number of tightly docked presynaptic vesicles, is reduced by about half in the BBBd hippocampus. These pathophysiologic changes are likely to contribute significantly to disturbed fast oscillatory activity, like cognition-associated gamma oscillations or sharp wave ripples and epileptogenesis in the BBBd hippocampus.

Cell-type specific inhibitory plasticity in subicular pyramidal cells.

The balance between excitation and inhibition is essential to the proper function of cortical circuits. To maintain this balance during dynamic network activity, modulation of the strength of inhibitory synapses is a central requirement. In this study, we aimed to characterize perisomatic inhibition and its plasticity onto pyramidal cells (PCs) in the subiculum, the main output region of the hippocampus. We performed whole-cell patch-clamp recordings from the two main functional PC types, burst (BS) and regular spiking (RS) neurons in acute rat hippocampal slices and applied two different extracellular high-frequency stimulation paradigms: non-associative (presynaptic stimulation only) and associative stimulation (concurrent pre-and postsynaptic stimulation) to induce plasticity. Our results revealed cell type-specific differences in the expression of inhibitory plasticity depending on the induction paradigm: While associative stimulation caused robust inhibitory plasticity in both cell types, non-associative stimulation produced long-term potentiation in RS, but not in BS PCs. Analysis of paired-pulse ratio, variance of IPSPs, and postsynaptic Ca2+ buffering indicated a dominant postsynaptic calcium-dependent signaling and expression of inhibitory plasticity in both PC types. This divergence in inhibitory plasticity complements a stronger inhibition and a higher intrinsic excitability in RS as compared to BS neurons, suggesting differential involvement of the two PC types during network activation and information processing in the subiculum.

Age-Related Deficits in Binaural Hearing: Contribution of Peripheral and Central Effects.

Pure-tone audiograms often poorly predict elderly humans' ability to communicate in everyday complex acoustic scenes. Binaural processing is crucial for discriminating sound sources in such complex acoustic scenes. The compromised perception of communication signals presented above hearing threshold has been linked to both peripheral and central age-related changes in the auditory system. Investigating young and old Mongolian gerbils of both sexes, an established model for human hearing, we demonstrate age-related supra-threshold deficits in binaural hearing using behavioral, electrophysiological, anatomical, and imaging methods. Binaural processing ability was measured as the binaural masking level difference (BMLD), an established measure in human psychophysics. We tested gerbils behaviorally with "virtual headphones," recorded single-unit responses in the auditory midbrain and evaluated gross midbrain and cortical responses using positron emission tomography (PET) imaging. Furthermore, we obtained additional measures of auditory function based on auditory brainstem responses, auditory-nerve synapse counts, and evidence for central inhibitory processing revealed by PET. BMLD deteriorates already in middle-aged animals having normal audiometric thresholds and is even worse in old animals with hearing loss. The magnitude of auditory brainstem response measures related to auditory-nerve function and binaural processing in the auditory brainstem also deteriorate. Furthermore, central GABAergic inhibition is affected by age. Because the number of synapses in the apical turn of the inner ear was not reduced in middle-aged animals, we conclude that peripheral synaptopathy contributes little to binaural processing deficits. Exploratory analyses suggest increased hearing thresholds, altered binaural processing in the brainstem and changed central GABAergic inhibition as potential contributors.

Neuronal K+-Cl- cotransporter KCC2 as a promising drug target for epilepsy treatment.

Epilepsy is a prevalent neurological disorder characterized by unprovoked seizures. γ-Aminobutyric acid (GABA) serves as the primary fast inhibitory neurotransmitter in the brain, and GABA binding to the GABAA receptor (GABAAR) regulates Cl- and bicarbonate (HCO3-) influx or efflux through the channel pore, leading to GABAergic inhibition or excitation, respectively. The neuron-specific K+-Cl- cotransporter 2 (KCC2) is essential for maintaining a low intracellular Cl- concentration, ensuring GABAAR-mediated inhibition. Impaired KCC2 function results in GABAergic excitation associated with epileptic activity. Loss-of-function mutations and altered expression of KCC2 lead to elevated [Cl-]i and compromised synaptic inhibition, contributing to epilepsy pathogenesis in human patients. KCC2 antagonism studies demonstrate the necessity of limiting neuronal hyperexcitability within the brain, as reduced KCC2 functioning leads to seizure activity. Strategies focusing on direct (enhancing KCC2 activation) and indirect KCC2 modulation (altering KCC2 phosphorylation and transcription) have proven effective in attenuating seizure severity and exhibiting anti-convulsant properties. These findings highlight KCC2 as a promising therapeutic target for treating epilepsy. Recent advances in understanding KCC2 regulatory mechanisms, particularly via signaling pathways such as WNK, PKC, BDNF, and its receptor TrkB, have led to the discovery of novel small molecules that modulate KCC2. Inhibiting WNK kinase or utilizing newly discovered KCC2 agonists has demonstrated KCC2 activation and seizure attenuation in animal models. This review discusses the role of KCC2 in epilepsy and evaluates its potential as a drug target for epilepsy treatment by exploring various strategies to regulate KCC2 activity.

Low glycemic index diet restrains epileptogenesis in a gender-specific fashion.

Dietary restriction, such as low glycemic index diet (LGID), have been successfully used to treat drug-resistant epilepsy. However, if such diet could also counteract antiepileptogenesis is still unclear. Here, we investigated whether the administration of LGID during the latent pre-epileptic period, prevents or delays the appearance of the overt epileptic phenotype. To this aim, we used the Synapsin II knockout (SynIIKO) mouse, a model of temporal lobe epilepsy in which seizures manifest 2-3 months after birth, offering a temporal window in which LGID may affect epileptogenesis. Pregnant SynIIKO mice were fed with either LGID or standard diet during gestation and lactation. Both diets were maintained in weaned mice up to 5 months of age. LGID delayed the seizure onset and induced a reduction of seizures severity only in female SynIIKO mice. In parallel with the epileptic phenotype, high-density multielectrode array recordings revealed a reduction of frequency, amplitude, duration, velocity of propagation and spread of interictal events by LGID in the hippocampus of SynIIKO females, but not mutant males, confirming the gender-specific effect. ELISA-based analysis revealed that LGID increased cortico-hippocampal allopregnanolone (ALLO) levels only in females, while it was unable to affect ALLO plasma concentrations in either sex. The results indicate that the gender-specific interference of LGID with the epileptogenic process can be ascribed to a gender-specific increase in cortical ALLO, a neurosteroid known to strengthen GABAergic transmission. The study highlights the possibility of developing a personalized gender-based therapy for temporal lobe epilepsy.

Compensatory changes in GABAergic inhibition are differentially expressed in the respiratory network to promote function following hibernation.

The respiratory network must produce consistent output throughout an animal's life. Although respiratory motor plasticity is well appreciated, how plasticity mechanisms are organized to give rise to robustness following perturbations that disrupt breathing is less clear. During underwater hibernation, respiratory neurons of bullfrogs remain inactive for months, providing a large disturbance that must be overcome to restart breathing. As a result, motoneurons upregulate excitatory synapses to promote the drive to breathe. Reduced inhibition often occurs in parallel with increased excitation, yet the loss of inhibition can destabilize respiratory motor output. Thus, we hypothesized that GABAergic inhibition would decrease following hibernation, but this decrease would be expressed differentially throughout the network. We confirmed that respiratory frequency was under control of GABAAR signaling, but after hibernation, it became less reliant on inhibition. The loss of inhibition was confined to the respiratory rhythm-generating centers: non-respiratory motor activity and large seizure-like bursts were similarly triggered by GABAA receptor blockade in controls and hibernators. Supporting reduced presynaptic GABA release, firing rate of respiratory motoneurons was constrained by a phasic GABAAR tone, but after hibernation, this tone was decreased despite the same postsynaptic receptor strength as controls. Thus, selectively reducing inhibition in respiratory premotor networks promotes stability of breathing, while wholesale loss of GABAARs causes non-specific hyperexcitability throughout the brainstem. These results suggest that different parts of the respiratory network select distinct strategies involving either excitation (motoneurons) or inhibition (rhythm generator) to minimize pathological network states when engaging plasticity that protects the drive to breathe.

An imbalance of excitation and inhibition in the multisensory cortex impairs the temporal acuity of audiovisual processing and perception.

The neural integration of closely timed auditory and visual stimuli can offer several behavioral advantages; however, an overly broad window of temporal integration-a phenomenon observed in various neurodevelopmental disorders-could have far-reaching perceptual consequences. Non-invasive studies in humans have suggested that the level of GABAergic inhibition in the multisensory cortex influences the temporal window over which auditory and visual stimuli are bound into a unified percept. Although this suggestion aligns with the theory that an imbalance of cortical excitation and inhibition alters multisensory processing, no prior studies have performed experimental manipulations to determine the causal effects of a reduction of GABAergic inhibition on audiovisual temporal perception. To that end, we used a combination of in vivo electrophysiology, neuropharmacology, and translational behavioral testing in rats to provide the first mechanistic evidence that a reduction of GABAergic inhibition in the audiovisual cortex is sufficient to disrupt unisensory and multisensory processing across the cortical layers, and ultimately impair the temporal acuity of audiovisual perception and its rapid adaptation to recent sensory experience. Looking forward, our findings provide support for using rat models to further investigate the neural mechanisms underlying the audiovisual perceptual alterations observed in neurodevelopmental disorders, such as autism, schizophrenia, and dyslexia.

Early-life propofol exposure does not affect later-life GABAergic inhibition, seizure induction, or social behavior.

The early developing brain is especially vulnerable to anesthesia, which can result in long lasting functional changes. We examined the effects of early-life propofol on adult excitatory-inhibitory balance and behavior. Postnatal day 7 male mice were exposed to propofol (250 mg/kg i.p.) and anesthesia was maintained for 2 h; control mice were given the same volume of isotonic saline and treated identically. The behavior and electrophysiology experiments were conducted when the mice were adults. We found that a 2-h neonatal propofol exposure did not significantly reduce paired pulse inhibition, alter the effect of muscimol (3 µM) to inhibit field excitatory postsynaptic potentials or alter the effect of bicuculline (100 µM) to increase the population spike in the CA1 region of hippocampal slices from adult mice. Neonatal propofol did not alter the evoked seizure response to pentylenetetrazol in adult mice. Neonatal propofol did not affect anxiety, as measured in the open field apparatus, depression-like behavior, as measured by the forced swim test, or social interactions with novel mice, in either the three-chamber or reciprocal social tests. These results were different from those with neonatal sevoflurane which demonstrated reduced adult GABAergic inhibition, increased seizure susceptibility and reduced social interaction. Even though sevoflurane and propofol both prominently enhance GABA inhibition, they have unique properties that alter the long-term effects of early-life exposure. These results indicate that clinical studies grouping several general anesthetic agents in a single group should be interpreted with great caution when examining long-term effects.

Spatial-dependent suppressive aftereffect produced by a sound in the rat's inferior colliculus is partially dependent on local inhibition.

In a natural acoustic environment, a preceding sound can suppress the perception of a succeeding sound which can lead to auditory phenomena such as forward masking and the precedence effect. The degree of suppression is dependent on the relationship between the sounds in sound quality, timing, and location. Correlates of such phenomena exist in sound-elicited activities of neurons in hearing-related brain structures. The present study recorded responses to pairs of leading-trailing sounds from ensembles of neurons in the rat's inferior colliculus. Results indicated that a leading sound produced a suppressive aftereffect on the response to a trailing sound when the two sounds were colocalized at the ear contralateral to the site of recording (i.e., the ear that drives excitatory inputs to the inferior colliculus). The degree of suppression was reduced when the time gap between the two sounds was increased or when the leading sound was relocated to an azimuth at or close to the ipsilateral ear. Local blockage of the type-A γ-aminobutyric acid receptor partially reduced the suppressive aftereffect when a leading sound was at the contralateral ear but not at the ipsilateral ear. Local blockage of the glycine receptor partially reduced the suppressive aftereffect regardless of the location of the leading sound. Results suggest that a sound-elicited suppressive aftereffect in the inferior colliculus is partly dependent on local interaction between excitatory and inhibitory inputs which likely involves those from brainstem structures such as the superior paraolivary nucleus. These results are important for understanding neural mechanisms underlying hearing in a multiple-sound environment.

Multisession Anodal Transcranial Direct Current Stimulation Enhances Adult Hippocampal Neurogenesis and Context Discrimination in Mice.

Transcranial direct current stimulation (tDCS) is a promising noninvasive neuromodulatory treatment option for multiple neurologic and psychiatric disorders, but its mechanism of action is still poorly understood. Adult hippocampal neurogenesis (AHN) continues throughout life and is crucial for preserving several aspects of hippocampal-dependent cognitive functions. Nevertheless, the contribution of AHN in the neuromodulatory effects of tDCS remains unexplored. Here, we sought to investigate whether multisession anodal tDCS may modulate AHN and its associated cognitive functions. Multisession anodal tDCS were applied on the skull over the hippocampus of adult male mice for 20 min at 0.25 mA once daily for 10 d totally. We found that multisession anodal tDCS enhances AHN by increasing the proliferation, differentiation and survival of neural stem/progenitor cells (NSPCs). In addition, tDCS treatment increased cell cycle reentry and reduced cell cycle exit of NSPCs. The tDCS-treated mice exhibited a reduced GABAergic inhibitory tone in the dentate gyrus compared with sham-treated mice. The effect of tDCS on the proliferation of NSPCs was blocked by pharmacological restoration of GABAB receptor-mediated inhibition. Functionally, multisession anodal tDCS enhances performance on a contextual fear discrimination task, and this enhancement was prevented by blocking AHN using the DNA alkylating agent temozolomide (TMZ). Our results emphasize an important role for AHN in mediating the beneficial effects of tDCS on cognitive functions that substantially broadens the mechanistic understanding of tDCS beyond its well-described in hippocampal synaptic plasticity.SIGNIFICANCE STATEMENT Transcranial direct current stimulation (tDCS) has been shown to effectively enhance cognitive functions in healthy and pathologic conditions. However, the mechanisms underlying its effects are largely unknown and need to be better understood to enable its optimal clinical use. This study shows that multisession anodal tDCS enhances adult hippocampal neurogenesis (AHN) and therefore contributes to enhance context discrimination in mice. Our results also show that the effect of tDCS on AHN is associated with reduced GABAergic inhibition in the dentate gyrus. Our study uncovers a novel mechanism of anodal tDCS to elicit cognitive-enhancing effects and may have the potential to improve cognitive decline associated with normal aging and neurodegenerative disorders.

GABAergic synaptic transmission and cortical oscillation patterns in the primary somatosensory area of a valproic acid rat model of autism spectrum disorder.

Autism spectrum disorder (ASD) is characterized by impaired social communication and interaction associated with repetitive or stereotyped behaviour. Prenatal valproic acid (VPA) exposure in rodents is a commonly used model of ASD. Resveratrol (RSV) has been shown to prevent interneuronal and behavioural impairments in the VPA model. We investigated the effects of prenatal VPA exposure and RSV on the GABAergic synaptic transmission, brain oscillations and on the genic expression of interneuron-associated transcription factor LHX6 in the primary somatosensory area (PSSA). Prenatal VPA exposure decreased the sIPSC and mIPSC frequencies and the sIPSC decay kinetics onto layers 4/5 pyramidal cells of PSSA. About 40% of VPA animals exhibited absence-like spike-wave discharge (SWD) events associated with behaviour arrest and increased power spectrum density of delta, beta and gamma cortical oscillations. VPA animals had reduced LHX6 expression in PSSA, but VPA animals treated with RSV had no changes on synaptic inhibition or LHX6 expression in the PSSA. SWD events associated with behaviour arrest and the abnormal increment of cortical oscillations were also absent in VPA animals treated with RSV. These findings provide new venues to investigate the role of both RSV and VPA in the pathophysiology of ASD and highlight the VPA animal model as an interesting tool to investigate pathways related to the aetiology and possible future therapies to this neuropsychiatric disorder.

The efficacy and safety of ganaxolone for the treatment of refractory epilepsy: A meta-analysis from randomized controlled trials.

OBJECTIVE: Epilepsy is one of the most common and refractory neurological disorders globally. Ganaxolone, a neuroactive steroid that enhances GABAergic inhibition, has been tested in many trials for the resolution of refractory epilepsy. Based on these, our study implemented a meta-analysis to evaluate the general benefit of ganaxolone for refractory epilepsy. METHODS: EMBASE, Medline, Scopus, Cochrane Library, and Clinicaltrials.gov were searched for relevant randomized controlled trials (RCTs) up to June 20, 2022. The risk ratio (RR) and standard mean difference (SMD) were analyzed using dichotomous and continuous outcomes, respectively with a random effect model. Trial sequential analysis (TSA) was also performed to judge the reliability of results. RESULTS: We totally collected 659 patients from four RCTs to evaluate the efficacy and safety of ganaxolone. As results showed, ≥50% reduction in mean seizure frequency has improved significantly compared with placebo (RR = 1.60, 95%CI: 1.02-2.49, p = 0.04, I2  = 30%), which is supported by TSA. However, the percentage of seizure-free days shows no statistical significance (p = 0.36). For safety outcomes, adverse events (AEs), serious adverse events, and AE leading to study drug discontinuation all revealed no obvious difference between ganaxolone and placebo (p > 0.05). SIGNIFICANCE: Based on our research, we have observed that ganaxolone is safe and has potential efficacy in the treatment of refractory epilepsy, waiting for further studies.

2-AG and anandamide enhance hippocampal long-term potentiation via suppression of inhibition.

It is widely accepted that exogenous cannabinoids can impair short-term memory and cognition in humans and other animals. This is likely related to the inhibition of long-term potentiation (LTP), a form of synaptic plasticity, by the global and sustained activation of CB1 cannabinoid receptors in the presence of exogenous agonists. Conversely, the temporally and spatially restricted release of endogenous cannabinoid (eCB) ligands may enhance synaptic plasticity in a synapse-specific manner. We examined the role of eCB signaling in LTP by recording field excitatory postsynaptic potentials (fEPSPs) in the CA1 stratum radiatum in hippocampal slices from juvenile mice. LTP was induced either electrically, by theta burst stimulation (TBS), or pharmacologically, by treatment for 15 min with a solution designed to increase intracellular cAMP (chem-LTP). A stable and long-lasting potentiation in fEPSP slope following TBS was significantly reduced by blocking cannabinoid receptor activation with CB1 receptor antagonists. Chem-LTP caused a sustained 2-fold increase in fEPSP slope and was also blocked by CB1 receptor antagonists. TBS-LTP was partially reduced by inhibiting the synthesis of the endogenous ligands 2-arachidonylglycerol (2-AG) and anandamide. A similar effect was observed with chem-LTP. Blocking inhibitory synapses completely prevented the effect of CB1 receptor antagonists or inhibition of eCB synthesis on TBS-LTP and chem-LTP. These results indicate that simultaneous activation of CB1 receptors by 2-AG and anandamide enhances TBS-induced and pharmacologically-induced LTP, and this effect is mediated by the suppression of inhibition at GABAergic synapses.

Preventing Phosphorylation of the GABA A R ß3 Subunit Compromises the Behavioral Effects of Neuroactive Steroids.

Neuroactive steroids (NASs) have potent anxiolytic, anticonvulsant, sedative, and hypnotic actions, that reflect in part their efficacy as GABA A R positive allosteric modulators (PAM). In addition to this, NAS exert metabotropic effects on GABAergic inhibition via the activation of membrane progesterone receptors (mPRs), which are G-protein coupled receptors. mPR activation enhances the phosphorylation of residues serine 408 and 409 (S408/9) in the ß3 subunit of GABA A Rs, increasing their accumulation in the plasma membrane leading to a sustained increase in tonic inhibition. To explore the significance of NAS-induced phosphorylation of GABA A Rs, we used mice in which S408/9 in the ß3 subunit have been mutated to alanines, mutations that prevent the metabotropic actions of NASs on GABA A R function while preserving NAS allosteric potentiation of GABAergic current. While the sedative actions of NAS were comparable to WT, their anxiolytic actions were reduced in S408/9A mice. Although the induction of hypnosis by NAS were maintained in the mutant mice the duration of the loss of righting reflex was significantly shortened. Finally, ability of NAS to terminate diazepam pharmacoresistant seizures was abolished in S408/9A mice. In conclusion, our results suggest that S408/9 in the GABA A R ß3 subunit contribute to the anxiolytic and anticonvulsant efficacy of NAS, in addition to their ability to regulate the loss of righting reflex.

The ATP Level in the Medial Prefrontal Cortex Regulates Depressive-like Behavior via the Medial Prefrontal Cortex-Lateral Habenula Pathway.

BACKGROUND: Depression is the most common mental illness. Mounting evidence suggests that dysregulation of extracellular ATP (adenosine triphosphate) is involved in the pathophysiology of depression. However, the cellular and neural circuit mechanisms through which ATP modulates depressive-like behavior remain elusive. METHODS: By use of ex vivo slice electrophysiology, chemogenetic manipulations, RNA interference, gene knockout, behavioral testing, and two depression mouse models, one induced by chronic social defeat stress and one caused by a IP3R2-null mutation, we systematically investigated the cellular and neural circuit mechanisms underlying ATP deficiency-induced depressive-like behavior. RESULTS: Deficiency of extracellular ATP in both defeated susceptible mice and IP3R2-null mutation mice led to reduced GABAergic (gamma-aminobutyric acidergic) inhibition and elevated excitability in lateral habenula-projecting, but not dorsal raphe-projecting, medial prefrontal cortex (mPFC) neurons. Furthermore, the P2X2 receptor in GABAergic interneurons mediated ATP modulation of lateral habenula-projecting mPFC neurons and depressive-like behavior. Remarkably, chemogenetic activation of the mPFC-lateral habenula pathway induced depressive-like behavior in C57BL/6J mice, while inhibition of this pathway was sufficient to alleviate the behavioral impairment in both defeated susceptible and IP3R2-null mutant mice. CONCLUSIONS: Overall, our study provides compelling evidence that ATP level in the mPFC is critically involved in regulating depressive-like behavior in a pathway-specific manner. These results shed new light on the mechanisms underlying depression and the antidepressant effect of ATP.

Interneuronal dynamics facilitate the initiation of spike block in cortical microcircuits.

Pyramidal cell spike block is a common occurrence in migraine with aura and epileptic seizures. In both cases, pyramidal cells experience hyperexcitation with rapidly increasing firing rates, major changes in electrochemistry, and ultimately spike block that temporarily terminates neuronal activity. In cortical spreading depression (CSD), spike block propagates as a slowly traveling wave of inactivity through cortical pyramidal cells, which is thought to precede migraine attacks with aura. In seizures, highly synchronized cortical activity can be interspersed with, or terminated by, spike block. While the identifying characteristic of CSD and seizures is the pyramidal cell hyperexcitation, it is currently unknown how the dynamics of the cortical microcircuits and inhibitory interneurons affect the initiation of hyperexcitation and subsequent spike block.We tested the contribution of cortical inhibitory interneurons to the initiation of spike block using a cortical microcircuit model that takes into account changes in ion concentrations that result from neuronal firing. Our results show that interneuronal inhibition provides a wider dynamic range to the circuit and generally improves stability against spike block. Despite these beneficial effects, strong interneuronal firing contributed to rapidly changing extracellular ion concentrations, which facilitated hyperexcitation and led to spike block first in the interneuron and then in the pyramidal cell. In all cases, a loss of interneuronal firing triggered pyramidal cell spike block. However, preventing interneuronal spike block was insufficient to rescue the pyramidal cell from spike block. Our data thus demonstrate that while the role of interneurons in cortical microcircuits is complex, they are critical to the initiation of pyramidal cell spike block. We discuss the implications that localized effects on cortical interneurons have beyond the isolated microcircuit and their contribution to CSD and epileptic seizures.

The critical period: neurochemical and synaptic mechanisms shared by the visual cortex and the brain stem respiratory system.

The landmark studies of Wiesel and Hubel in the 1960's initiated a surge of investigations into the critical period of visual cortical development, when abnormal visual experience can alter cortical structures and functions. Most studies focused on the visual cortex, with relatively little attention to subcortical structures. The goal of the present review is to elucidate neurochemical and synaptic mechanisms common to the critical periods of the visual cortex and the brain stem respiratory system in the normal rat. In both regions, the critical period is a time of (i) heightened inhibition; (ii) reduced expression of brain-derived neurotrophic factor (BDNF); and (iii) synaptic imbalance, with heightened inhibition and suppressed excitation. The last two mechanisms are contrary to the conventional premise. Synaptic imbalance renders developing neurons more vulnerable to external stressors. However, the critical period is necessary to enable each system to strengthen its circuitry, adapt to its environment, and transition from immaturity to maturity, when a state of relative synaptic balance is attained. Failure to achieve such a balance leads to neurological disorders.

In vivo evidence for the cellular basis of central hypoventilation of Rett syndrome and pharmacological correction in the rat model.

Rett syndrome (RTT) is a neurodevelopmental disorder caused mostly by mutations in the MECP2 gene. RTT patients show periodical hypoventilation attacks. The breathing disorder contributing to the high incidence of sudden death is thought to be due to depressed central inspiratory (I) activity via unknown cellular processes. Demonstration of such processes may lead to targets for pharmacological control of the RTT-type hypoventilation. We performed in vivo recordings from medullary respiratory neurons on the RTT rat model. To our surprise, both I and expiratory (E) neurons in the ventral respiratory column (VRC) increased their firing activity in Mecp2-null rats with severe hypoventilation. These I neurons including E-I phase-spanning and other I neurons remained active during apneas. Consistent with enhanced central I drive, ectopic phrenic discharges during expiration as well as apnea were observed in the Mecp2-null rats. Considering the increased I neuronal firing and ectopic phrenic activity, the RTT-type hypoventilation does not seem to be caused by depression in central I activity, neither reduced medullary I premotor output. This as well as excessive E neuronal firing as shown in our previous studies suggests inadequate synaptic inhibition for phase transition. We found that the abnormal respiratory neuronal firing, ectopic phrenic discharge as well as RTT-type hypoventilation all can be corrected by enhancing GABAergic inhibition. More strikingly, Mecp2-null rats reaching humane endpoints with severe hypoventilation can be rescued by GABAergic augmentation. Thus, defective GABAergic inhibition among respiratory neurons is likely to play a role in the RTT-type hypoventilation, which can be effectively controlled with pharmacological agents.

Functional Interactions between Sensory and Memory Networks for Adaptive Behavior.

The brain's capacity to adapt to sensory inputs is key for processing sensory information efficiently and interacting in new environments. Following repeated exposure to the same sensory input, brain activity in sensory areas is known to decrease as inputs become familiar, a process known as adaptation. Yet, the brain-wide mechanisms that mediate adaptive processing remain largely unknown. Here, we combine multimodal brain imaging (functional magnetic resonance imaging [fMRI], magnetic resonance spectroscopy) with behavioral measures of orientation-specific adaptation (i.e., tilt aftereffect) to investigate the functional and neurochemical mechanisms that support adaptive processing. Our results reveal two functional brain networks: 1) a sensory-adaptation network including occipital and dorsolateral prefrontal cortex regions that show decreased fMRI responses for repeated stimuli and 2) a perceptual-memory network including regions in the parietal memory network (PMN) and dorsomedial prefrontal cortex that relate to perceptual bias (i.e., tilt aftereffect). We demonstrate that adaptation relates to increased occipito-parietal connectivity, while decreased connectivity between sensory-adaptation and perceptual-memory networks relates to GABAergic inhibition in the PMN. Thus, our findings provide evidence that suppressive interactions between sensory-adaptation (i.e., occipito-parietal) and perceptual-memory (i.e., PMN) networks support adaptive processing and behavior, proposing a key role of memory systems in efficient sensory processing.

Cortical disinhibitory circuits: cell types, connectivity and function.

The concept of a dynamic excitation/inhibition balance tuned by circuit disinhibition, which can shape information flow during complex behavioral tasks, has arisen as an important and conserved information-processing motif. In cortical circuits, different subtypes of GABAergic inhibitory interneurons are connected to each other, offering an anatomical foundation for disinhibitory processes. Moreover, a subpopulation of GABAergic cells that express vasoactive intestinal polypeptide (VIP) preferentially innervates inhibitory interneurons, highlighting their central role in disinhibitory modulation. We discuss inhibitory neuron subtypes involved in disinhibition, with a focus on local circuits and long-range synaptic connections that drive disinhibitory function. We highlight multiple layers of disinhibition across cortical circuits that regulate behavior and serve to maintain an excitation/inhibition balance.