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This study is the first report to suggest that activation of the Cl− transporter K+-Cl− cotransporter 2 may be a therapeutic modality for the treatment of spinal cord injury-induced detrusor overactivity by targeting bladder efferent pathways.

KCNB1 encodes the α-subunit of Kv2.1, the main contributor to neuronal delayed rectifier potassium currents. The subunit consists of six transmembrane α helices (S1-S6), comprising the voltage-sensing domain (S1-S4) and the pore domain (S5-P-S6). Heterozygous KCNB1 pathogenic variants are associated with developmental and epileptic encephalopathy. Here we report an individual who shows the milder phenotype compared to the previously reported cases, including delayed language development, mild intellectual disability, attention deficit hyperactivity disorder, late-onset epilepsy responsive to an antiepileptic drug, elevation of serum creatine kinase, and peripheral axonal neuropathy. On the other hand, his brain MRI showed characteristic findings including periventricular heterotopia, polymicrogyria, and abnormal corpus callosum. Exome sequencing identified a novel de novo KCNB1 variant c.574GA, p.(Ala192Thr) located in the S1 segment of the voltage-sensing domain. Functional analysis using the whole-cell patch-clamp technique in Neuro2a cells showed that the Ala192Thr mutant reduces both activation and inactivation of the channel at membrane voltages in the range of -50 to -30 mV. Our case could expand the phenotypic spectrum of patients with KCNB1 variants, and suggested that variants located in the S1 segment might be associated with a milder outcome of seizures.

Recently, we have identified CaMKIIα and CaMKIIβ mutations in patients with neurodevelopmental disorders by whole exome sequencing study. Most CaMKII mutants have increased phosphorylation of Thr286/287, which induces autonomous activity of CaMKII, using cell culture experiments. In this study, we explored the pathological mechanism of motor dysfunction observed exclusively in a patient with Pro213Leu mutation in CaMKIIβ using a mouse model of the human disease. The homozygous CaMKIIβ Pro213Leu knockin mice showed age-dependent motor dysfunction and growth failure from 2 weeks after birth. In the cerebellum, the mutation did not alter the mRNA transcript level, but the CaMKIIβ protein level was dramatically decreased. Furthermore, in contrast to previous result from cell culture, Thr287 phosphorylation of CaMKIIβ was also reduced. CaMKIIβ Pro213Leu knockin mice showed similar motor dysfunction as CaMKIIβ knockout mice, newly providing evidence for a loss of function rather than a gain of function. Our disease model mouse showed similar phenotypes of the patient, except for epileptic seizures. We clearly demonstrated that the pathological mechanism is a reduction of mutant CaMKIIβ in the brain, and the physiological aspects of mutation were greatly different between in vivo and cell culture.

Inappropriate synaptic development has been proposed as a potential mechanism of neurodevelopmental disorders, including attention-deficit hyperactivity disorder (ADHD). Major histocompatibility complex class I (MHCI), an immunity-associated molecule expressed by neurons in the brain, regulates synaptic development; however, the involvement of MHCI in these disorders remains elusive. We evaluated whether functional MHCI deficiency induced by β2m-/-Tap1-/- double-knockout in mice leads to abnormalities akin to those seen in neurodevelopmental disorders. We found that functional MHCI deficiency induced locomotor hyperactivity, motor impulsivity, and attention deficits, three major symptoms of ADHD. In contrast, these mice showed normal spatial learning, behavioral flexibility, social behavior, and sensorimotor integration. In the analysis of the dopamine system, upregulation of dopamine D1 receptor (D1R) expression in the nucleus accumbens and a greater locomotor response to D1R agonist SKF 81297 were found in the functional MHCI-deficient mice. Low-dose methylphenidate, used for the treatment of ADHD patients, alleviated the three behavioral symptoms and suppressed c-Fos expression in the D1R-expressing medium spiny neurons of the mice. These findings reveal an unexpected role of MHCI in three major symptoms of ADHD and may provide a novel landmark in the pathogenesis of ADHD.

Vacuolar H+-ATPases (V-ATPases) transport protons across cellular membranes to acidify various organelles. ATP6V0A1 encodes the a1-subunit of the V0 domain of V-ATPases, which is strongly expressed in neurons. However, its role in brain development is unknown. Here we report four individuals with developmental and epileptic encephalopathy with ATP6V0A1 variants: two individuals with a de novo missense variant (R741Q) and the other two individuals with biallelic variants comprising one almost complete loss-of-function variant and one missense variant (A512P and N534D). Lysosomal acidification is significantly impaired in cell lines expressing three missense ATP6V0A1 mutants. Homozygous mutant mice harboring human R741Q (Atp6v0a1R741Q) and A512P (Atp6v0a1A512P) variants show embryonic lethality and early postnatal mortality, respectively, suggesting that R741Q affects V-ATPase function more severely. Lysosomal dysfunction resulting in cell death, accumulated autophagosomes and lysosomes, reduced mTORC1 signaling and synaptic connectivity, and lowered neurotransmitter contents of synaptic vesicles are observed in the brains of Atp6v0a1A512P/A512P mice. These findings demonstrate the essential roles of ATP6V0A1/Atp6v0a1 in neuronal development in terms of integrity and connectivity of neurons in both humans and mice.

γ-Aminobutyric acid (GABA) generally induces hyperpolarization and inhibition in the adult brain, but causes depolarization (and can be excitatory) in the immature brain. Depolarizing GABA actions are necessary for neurogenesis, differentiation, migration, and synaptogenesis. Additionally, the conversion of GABA responses from inhibition to excitation can be induced in adults by pathological conditions. Because GABAA receptors are Cl- channels, alternating GABA actions between hyperpolarization (Cl- influx) and depolarization (Cl- efflux) are induced by changes in the Cl- gradient, which is regulated by C- transporters. Thus, the dynamics of neural functions are modulated by active Cl- homeostasis (Cl- homeodynamics), alternating inhibition and excitation, and could underlie the modal shifts in cellular and network oscillations. Such a modal shift in GABA actions is required for normal development. Thus disturbances in this developmental GABA modal shift and/or the induction of excitatory GABA action in adult could underlie the pathogenesis of diverse neurological diseases (so-called network diseases).

The intracellular Cl¯ concentration ([Cl¯]i) is tightly regulated in brain neurons for stabilizing brain performance. The [Cl¯]i in mature neurons is determined by the balance between the rate of Cl¯ extrusion mainly mediated by the neuron-specific type 2 K⁺-Cl¯ cotransporter (KCC2) and the rate of Cl¯ entry through various Cl¯ channels including GABAA receptors during neuronal activity. Disturbance of the balance causes instability of brain circuit performance and may lead to epileptic seizures. In the first part of this review, we discuss how genetic alterations in KCC2 in humans cause infantile migrating focal seizures, based on our previous report and others. Depolarization of the membrane potential increases the driving force for Cl¯ entry into neurons. Thus, the duration of action potential spike generation and the frequency of excitatory synaptic inputs are the crucial factors for determining the total amount of Cl¯ entry and the equilibrium [Cl¯]i in neurons. Moreover, there is also a significant interdependence between the neuronal activity and the KCC2 expression. In the second part, we discuss plausible mechanisms by which excessive neuronal activity due to excitotoxic brain insults or other epilepsy-associated gene mutations may cause the Cl¯ imbalance in neurons and lead to epileptic discharges over the brain, using the schematic “unifying foci” model based on literature.

Angelman syndrome is a neurodevelopmental disorder caused by loss of function of the maternally expressed UBE3A gene. Treatments for the main manifestations, including cognitive dysfunction or epilepsy, are still under development. Recently, the Cl- importer Na+-K+-Cl- cotransporter 1 (NKCC1) has gained attention as a therapeutic target in many neurological disorders. Dysregulation of neuronal intracellular Cl- concentration ([Cl-]i) is generally regarded as one of the mechanisms underlying neuronal dysfunction caused by the activation of brain NKCC1. Here, we analyzed the regulation of [Cl-]i and the effects of bumetanide, an NKCC1 inhibitor, in Angelman syndrome models (Ube3am-/p+ mice). We observed increased NKCC1 expression in the hippocampus of Ube3am-/p+ mice. The average [Cl-]i of CA1 pyramidal neurons was not significantly different, but demonstrated greater variance in Ube3am-/p+ mice. Tonic GABAA receptor-mediated Cl- conductance was reduced, which may have contributed to maintaining the normal average [Cl-]i. Bumetanide administration restores cognitive dysfunction in Ube3am-/p+ mice. Seizure susceptibility was also reduced regardless of the genotype. These results suggest that aberrantly activated NKCC1 has a pathophysiological impact, leading to cognitive dysfunction in Ube3am-/p+ mice, although the average [Cl-]i is not altered. The blockage of NKCC1 may be a potential therapeutic strategy for patients with Angelman syndrome.

Electrical activity plays crucial roles in neural circuit formation and remodeling. During neocortical development, neurons are generated in the ventricular zone, migrate to their correct position, elongate dendrites and axons, and form synapses. In this review, we summarize the functions of ion channels and transporters in neocortical development. Next, we discuss links between neurological disorders caused by dysfunction of ion channels (channelopathies) and neocortical development. Finally, we introduce emerging optical techniques with potential applications in physiological studies of neocortical development and the pathophysiology of channelopathies.

Fetal and infant brains are rich in maternally derived taurine. We previously demonstrated that taurine action regulates the cation-chloride cotransporter activity and the differentiation and radial migration of pyramidal neuron progenitors in the developing neocortex of rodent fetuses. Here we examined the effects of fetal and infantile taurine depletion caused by knockout of the taurine transporter Slc6a6 on firing properties of layer II/III pyramidal neurons in the mouse somatosensory cortex at 3 weeks of postnatal age, using the whole-cell patch-clamp technique. The membrane excitability under resting conditions was similar between the neurons in knockout mice and those in wildtype littermates. However, the frequency of repetitive spike firing during moderate current injection was significantly lower, along with lower membrane voltage levels during interspike intervals in knockout neurons. When strong currents were injected, by which repetitive firing was rapidly abolished due to inactivation of voltage-gated Na+ channels in wildtype neurons, the firing in knockout neurons lasted for a much longer period than in wildtype neurons. This was due to much lower membrane voltage levels during interspike intervals in knockout neurons, promoting greater recovery of voltage-gated Na+ channels from inactivation. Thus, taurine depletion in pyramidal neurons blunted neuronal responses to external stimuli through increasing the stability of repetitive firing, presumably mediated by larger increases in membrane K+ conductance during interspike intervals.

We studied the electric-field-induced tilt angle in SmA of MC881 and found the field-induced, first-order phase transition to SmC∗ in the SmA temperature region just above temperature-induced antif...

Prompted by the existence of biaxial subphases 1/4, 2/5, and 3/7 [Phys. Rev. E 96, 012701 (2017)2470-004510.1103/PhysRevE.96.012701], we reconsidered the three-phase frustration and the resulting degeneracy lifting by combining the phase diagram of SmC_{A}^{*}, SmC^{*}, and SmA with the discrete flexoelectric effect. We systematically calculated the phase diagrams and tried to understand the overall picture of the phenomena by means of a simple and intuitively clear way in terms of minimal number of parameters. The treatment naturally explains the highly distorted helical structures of the biaxial subphases as well as the microscopic helical short-pitch of SmC_{α}^{*} which increases or decreases accordingly with rising temperature. The regular subphase emerging sequence is SmC_{A}^{*}(SmC_{α}^{*})-1/4-1/3-2/5-3/7-1/2-SmC^{*}(SmC_{α}^{*}), where the subphases other than 1/3 and 1/2 may or may not emerge. At the same time, we can see a variety of irregular sequences; in particular, any one of the biaxial subphases may singly emerge between SmC_{A}^{*}(SmC_{α}^{*}) and (SmC^{*})SmC_{α}^{*}. Moreover, the experimentally confirmed extraordinary subphase emerging sequence SmC^{*}-1/2-SmC_{α}^{*} appears for particular parameter values. Contrastingly to these affirmative aspects, some calculated results are contradictory to the previously reported experimental results: the change from SmC_{A}^{*} and SmC^{*} to SmC_{α}^{*} is always continuous, the 6-layer 2/3 subphase is not stabilized, and the subphase emerging sequence SmC_{A}^{*}-1/3-SmC^{*} does not appear. The causes of inconsistency and how to resolve them were discussed in comparisons with experimental findings.

Temporal specification of the neural progenitors (NPs) producing excitatory glutamatergic neurons is essential for histogenesis of the cerebral cortex. Neuroepithelial cells, the primary NPs, transit to radial glia (RG). To coincide with the transition, NPs start to differentiate into neurons, undergoing a switch from symmetric to asymmetric cell division. After the onset of neurogenesis, NPs produce layer-specific neurons in a defined order with precise timing. Here, we show that GABAA receptors (GABAARs) and taurine are involved in this regulatory mechanism. Foetal exposure to GABAAR-antagonists suppressed the transition to RG, switch to asymmetric division, and differentiation into upper-layer neurons. Foetal exposure to GABAAR-agonists caused the opposite effects. Mammalian foetuses are dependent on taurine derived from the mothers. GABA and taurine function as endogenous ligands for GABAARs. Ca2+ imaging showed that NPs principally responded to taurine but not GABA before E13. The histological phenotypes of the taurine transporter knockout mice resembled those of the mice foetally exposed to GABAAR-antagonists. Foetal exposure to GABAAR-modulators resulted in considerable alterations in offspring behavior like core symptoms of autism. These results show that taurine regulates the temporal specification of NPs and that disrupting the taurine-receptor interaction possibly leads to neurodevelopmental disorders.

Gamma-aminobutyric acid (GABA) generally induces hyperpolarization and inhibition in the adult brain, but causes depolarization (and can be excitatory) in the immature brain. Because GABAsubA/subreceptors are Clsup-/supchannels, alternating GABA actions between hyperpolarization (Clsup-/supinflux) and depolarization (Clsup-/supefflux) are induced by changes in the Clsup-/supgradient, which is regulated by Clsup-/suptransporters. Thus, the dynamics of neural functions are modulated by "active" Clsup-/suphomeostasis (Clsup-/suphomeodynamics), alternating inhibition and excitation, and could be the underlying mechanism of modal shifts in cellular and network oscillations. An ontogenic modal shift in GABA actions is required for normal development, but an aversive reverse modal shift in adults could occur occasionally. Thus any disturbance in this ordinal developmental GABA modal shift, resulting in an abnormal temporal window of depolarizing (excitatory) GABA action, could be the underlying pathogenesis of diverse neurodevelopmental disorders and neurological diseases.

The chiral smectic phases of calamitic liquid crystals, $\mathrm{Sm}{C}^{*}$ and $\mathrm{Sm}{C}_{A}^{*}$, are characterized by the synclinic ferroelectric $F$ ordering and the anticlinic antiferroelectric $A$ ordering in adjacent layers. Various states with mixed $A$ and $F$ orderings are degenerate at the frustrated phase-transition point. The degeneracy lifting is commonly caused by the long-range interlayer interactions (LRILIs), producing a series of biaxial subphases specified by a relative ratio of both orderings, ${q}_{T}=[F]/([A]+[F])$. Sandhya et al. [Phys. Rev. E 87, 012502 (2013)] established, however, the importance of thermal fluctuations in the degeneracy lifting in some binary mixtures of MC881 and MC452. They observed the most intriguing interplay of thermal fluctuations and LRILIs in the stabilization of an apparently single subphase. Since no other detailed experimental study of the subphase has so far been made, we carry out its dielectric investigations and clarify the following five points: (1) the subphase is surely a single phase from $\ensuremath{\approx}80{\phantom{\rule{0.16em}{0ex}}}^{\ensuremath{\circ}}\mathrm{C}$ down to room temperature; (2) the imaginary part of complex permittivity ${\ensuremath{\epsilon}}^{\ensuremath{''}}$ shows the weak antiphase mode and hence it must be antiferroelectric ${q}_{T}=1/2$; (3) ${\ensuremath{\epsilon}}^{\ensuremath{''}}$ becomes much stronger above $\ensuremath{\approx}80{\phantom{\rule{0.16em}{0ex}}}^{\ensuremath{\circ}}\mathrm{C}$, indicating the emergence of ferroelectric and/or ferrielectric states; (4) the dielectric amplitude gradually increases at least just above the 1/2 subphase, suggesting it be due to a continuous increase of ${q}_{T}$; and (5) at low temperatures the antiphase relaxation mode shows irregularities that indicate the important role played by the cooperative motion of the layer undulation as well as of the director tilting.

The intracellular Cl

Animal models are needed to gain an understanding of the genetic, molecular, cellular, and network mechanisms of human brain development. In rodents, a large spectrum of in vitro and in vivo approaches allows detailed analyses and specific experimental manipulations for studying the sequence of developmental steps in corticogenesis. Neurogenesis, neuronal migration, cellular differentiation, programmed cell death, synaptogenesis, and myelination are surprisingly similar in the rodent cortex and the human cortex. Spontaneous EEG activity in the pre- and early postnatal human cortex resembles the activity patterns recorded with intracortical multi-electrode arrays in newborn rodents. This early activity is generated by thalamic activation of a subplate-driven local network coupled via gap junctions, which controls the development of cortical columns and the spatio-temporal pattern of apoptosis. Disturbances of this activity may induce disturbances in cortical structure and function leading to neurological and psychiatric disorders.

A selenium-containing compound, AS657, is studied with two complementary methods, electric-field-induced birefringence (EFIB) and microbeam resonant X-ray scattering (µRXS). AS657 shows a phase sequence of Sm – – – Sm – Sm where no Sm emerges and hence the frustration between Sm and Sm plays an important role. In spite of this situation, two additional temperature-induced subphases are observed: (1) antiferroelectric eight-layer between Sm and and (2) antiferroelectric 10-layer between and . A number of field-induced subphases are also shown to emerge. The most notable new finding is the observation of an electric-field-induced ferrielectric subphase of six-layer () between and Sm; this subphase is stabilised even at zero field in a mixture of 92.6 wt% AS657 and 7.4 wt% AS620. Another field-induced subphase of six-layer is also confirmed to emerge in the temperature ranges of SmCA* and . The nature of the field-induced transitions in the temperature range is more complex than previously thought; i...

Neuronal migration and maturation in the developing neocortex are tightly regulated by the intracellular Cl− level. Thus cation-chloride cotransporters, especially Na+–K+–2Cl− cotransporter 1 (NKCC1) and K+–Cl− cotransporter 2 (KCC2), play important roles in the regulation of those processes. In this chapter, we summarize the regulatory mechanisms of neuronal migration and maturation mediated by the transporter activities during embryonic and perinatal periods in the developing neocortex, based on recent literature using rodent models, and discuss the similarities and differences in the mechanisms between two different types of neuronal precursors, i.e., glutamatergic and GABAergic ones.

GABAA receptor chloride channels are widely known to mediate inhibitory neurotransmission in matured synapses. However, during the central nervous system development, its activation causes membrane-depolarization of immature neurons because of high intercellular Cl− concentrations and exhibits trophic effects. As well as dynamic changes in excitability, developmental changes in a variety of GABAA receptor subunit and phasic/tonic (extrasynaptic) actions bring the multimodality of GABAA receptor function. In this chapter, we describe the diversity of GABAA receptors, and how the multimodal functions of GABAA receptor contribute to various events of neuronal development: neurogenesis, neuronal migration, synaptogenesis during development. According to its importance during ontogeny, GABAA receptor–mediated signaling is implicated in a number of neurodevelopmental disorders such as schizophrenia, epilepsy, autism spectrum disorder, and Down syndrome. Thus, we also review the linkage between the multimodal functions of GABAA receptor and these disorders.

Na+-K+-2Cl− cotransporter (NKCC1) and neuron-specific K+-Cl− cotransporter (KCC2) are essential for Cl− homeostasis in the central nervous system. The intracellular Cl− concentration determines the polarity and strength of the GABA response. Although it is now well established that the activity of KCC2 and NKCC1 are changed in various physiological and pathophysiological conditions, the post-translational modification that regulate the function of KCC2 and NKCC1 is yet to be studied more intensely. Here we discuss the growing evidence of post-translational modification such as phosphorylation/dephosphorylation, glycosylation, oligomerization, and degradation, that rapidly and dynamically regulate the function of KCC2 and NKCC1.

Temporal specification of the neural progenitors (NPs) producing excitatory glutamatergic neurons is essential for histogenesis of the cerebral cortex. Neuroepithelial cells, the primary NPs, transit to radial glia (RG). To coincide with the transition, NPs start to differentiate into neurons, undergoing a switch from symmetric to asymmetric cell division. After the onset of neurogenesis, NPs produce layer-specific neurons in a defined order with precise timing. Here, we show that GABAA receptors (GABAARs) and taurine are involved in this regulatory mechanism. Foetal exposure to GABAAR-antagonists suppressed the transition to RG, switch to asymmetric division, and differentiation into upper-layer neurons. Foetal exposure to GABAAR-agonists caused the opposite effects. Mammalian foetuses are dependent on taurine derived from the mothers. GABA and taurine function as endogenous ligands for GABAARs. Ca2+ imaging showed that NPs principally responded to taurine but not GABA before E13. The histological phenotypes of the taurine transporter knockout mice resembled those of the mice foetally exposed to GABAAR-antagonists. Foetal exposure to GABAAR-modulators resulted in considerable alterations in offspring behavior like core symptoms of autism. These results show that taurine regulates the temporal specification of NPs and that disrupting the taurine-receptor interaction possibly leads to neurodevelopmental disorders.

Despite its importance for γ-aminobutyric acid (GABA) inhibition and involvement in neurodevelopmental disease, the regulatory mechanisms of the K(+)/Cl(−) co-transporter KCC2 (encoded by SLC12A5) during maturation of the central nervous system (CNS) are not entirely understood. Here, we applied quantitative phosphoproteomics to systematically map sites of KCC2 phosphorylation during CNS development in the mouse. KCC2 phosphorylation at Thr(906) and Thr(1007), which inhibits KCC2 activity, underwent dephosphorylation in parallel with the GABA excitatory-inhibitory sequence in vivo. Knock-in mice expressing the homozygous phospho-mimetic KCC2 mutations T906E/T1007E (Kcc2(E/E)), which prevented the normal developmentally regulated dephosphorylation of these sites, exhibited early postnatal death from respiratory arrest and a marked absence of cervical spinal neuron respiratory discharges. Kcc2(E/E) mice also displayed disrupted lumbar spinal neuron locomotor rhythmogenesis and touch-evoked status epilepticus associated with markedly impaired KCC2-dependent Cl(−) extrusion. These data identify a previously unknown phosphorylation-dependent KCC2 regulatory mechanism during CNS development that is essential for dynamic GABA-mediated inhibition and survival.

The unique nanometer-sized helical structure in SmC_{α}^{*} may sometimes evolve continuously to the micrometer-sized one in SmC^{*}; conceivably ferroelectric SmC_{α}^{*} is to be unwound by an applied electric field. By drawing electric-field-induced birefringence contours in the field-temperature phase diagram and by studying the superlattice structure of the field-induced subphase with resonant x-ray scattering, we established that an applied field unexpectedly stabilizes the well-known antiferroelectric four-layer biaxial subphase as well as the other prototypal ferrielectric three-layer one in the SmC_{α}^{*} temperature range; the effective long-range interlayer interaction due to the discrete flexoelectric effect actually plays an important role in stabilizing not only the biaxial subphases but also the optically uniaxial SmC_{α}^{*} subphase, contrary to the notion that the competition between the direct interactions of the nearest-neighbor layers and those of the next-nearest-neighbor layers should be required for the nanometer-sized helical structure.

Vacuolar H+-ATPases (V-ATPases) transport protons across cellular membranes to acidify various organelles. ATP6V0A1 encodes the a1-subunit of the V0 domain of V-ATPases, which is strongly expressed in neurons. However, its role in brain development is unknown. Here we report four individuals with developmental and epileptic encephalopathy with ATP6V0A1 variants: two individuals with a de novo missense variant (R741Q) and the other two individuals with biallelic variants comprising one almost complete loss-of-function variant and one missense variant (A512P and N534D). Lysosomal acidification is significantly impaired in cell lines expressing three missense ATP6V0A1 mutants. Homozygous mutant mice harboring human R741Q (Atp6v0a1R741Q) and A512P (Atp6v0a1A512P) variants show embryonic lethality and early postnatal mortality, respectively, suggesting that R741Q affects V-ATPase function more severely. Lysosomal dysfunction resulting in cell death, accumulated autophagosomes and lysosomes, reduced mTORC1 signaling and synaptic connectivity, and lowered neurotransmitter contents of synaptic vesicles are observed in the brains of Atp6v0a1A512P/A512P mice. These findings demonstrate the essential roles of ATP6V0A1/Atp6v0a1 in neuronal development in terms of integrity and connectivity of neurons in both humans and mice., A member of the vacuolar H+-ATPase family, ATP6V0A1 is involved in lysosomal activity. Here, the authors report that ATP6V0A1 variants identified in individuals with developmental and epileptic encephalopathy are associated with impairment of lysosomal acidification, autophagy and mTORC1 signaling, suggesting an essential role of ATP6V0A1 in brain development.

An imbalance of excitatory and inhibitory neurotransmission leading to over excitation plays a crucial role in generating seizures, while enhancing GABAergic mechanisms are critical in terminating seizures. In recent years, it has been reported in many studies that astrocytes are deeply involved in synaptic transmission. Astrocytes form a critical component of the “tripartite” synapses by wrapping around the pre- and post-synaptic elements. From this location, astrocytes are known to greatly influence the dynamics of ions and transmitters in the synaptic cleft. Despite recent extensive research on excitatory tripartite synapses, inhibitory tripartite synapses have received less attention, even though they influence inhibitory synaptic transmission by affecting chloride and GABA concentration dynamics. In this review, we will discuss the diverse actions of astrocytic chloride and GABA homeostasis at GABAergic tripartite synapses. We will then consider the pathophysiological impacts of disturbed GABA homeostasis at the tripartite synapse.

It has been found that electric field in free-standing smectic films at high temperature leads to formation of unusual 2π-walls, with quite different structure from the structure of classical 2π-walls. The walls are formed by the change of molecular orientation not only along the film plane (as in usual walls) but also in smectic layers between two surfaces of the film. These walls are nuclei of surface field-induced synclinic–anticlinic transition between states with transverse and longitudinal electric polarization.