SNARE protein SNAP25 regulates the chloride-transporter KCC2 in neurons.

Inhibitory synaptic neurotransmission mediated by GABA requires a low concentration of chloride ions (Cl) in neurons, which is established and maintained by the potassium-chloride co-transporter 2 (KCC2). While KCC2-interacting proteins are known to regulate KCC2 protein level and function, specific KCC2-interacting partners are still being identified and characterized. We asked whether SNAP25, an integral component of the SNARE-complex and a novel KCC2 interactor, regulates KCC2 protein and function in mice.

Restoring Compromised Cl in D2 Neurons of a Huntington's Disease Mouse Model Rescues Motor Disability.

Huntington's disease (HD) is a progressive neurodegenerative disorder with no cure, characterized by significant neurodegeneration of striatal GABAergic medium spiny neurons (MSNs). Early stages of the disease are characterized by the loss of dopamine 2 receptor-expressing MSNs (D2 MSNs) followed by degeneration of dopamine 1 receptor-expressing MSNs (D1 MSNs), leading to aberrant basal ganglia signaling. While the early degeneration of D2 MSNs and impaired GABAergic transmission are well-documented, potassium chloride cotransporter 2 (KCC2), a key regulator of intracellular chloride (Cl), and therefore GABAergic signaling, has not been characterized in D1 and D2 MSNs in HD.

LTP is Absent in the CA1 Region of the Hippocampus of Male and Female Rett Syndrome Mouse Models.

Rett syndrome (RTT) is a debilitating neurodevelopmental disorder caused by mutations in the X-linked methyl-CpG-binding protein 2 (MeCP2) gene, resulting in severe deficits in learning and memory. Alterations in synaptic plasticity have been reported in RTT, however most electrophysiological studies have been performed in male mice only, despite the fact that RTT is primarily found in females. In addition, most studies have focused on excitation, despite the emerging evidence for the important role of inhibition in learning and memory.

Chloride transporters controlling neuronal excitability.

Synaptic inhibition plays a crucial role in regulating neuronal excitability, which is the foundation of nervous system function. This inhibition is largely mediated by the neurotransmitters GABA and glycine that activate Cl-permeable ion channels, which means that the strength of inhibition depends on the Cl gradient across the membrane. In neurons, the Cl gradient is primarily mediated by two secondarily active cation-chloride cotransporters (CCCs), NKCC1 and KCC2.

Hippocampal-hypothalamic circuit controls context-dependent innate defensive responses.

Preys use their memory - where they sensed a predatory threat and whether a safe shelter is nearby - to dynamically control their survival instinct to avoid harm and reach safety. However, it remains unknown which brain regions are involved, and how such top-down control of innate behavior is implemented at the circuit level. Here, using adult male mice, we show that the anterior hypothalamic nucleus (AHN) is best positioned to control this task as an exclusive target of the hippocampus (HPC) within the medial hypothalamic defense system.

Corrigendum: Striatal Chloride Dysregulation and Impaired GABAergic Signaling Due to Cation-Chloride Cotransporter Dysfunction in Huntington's Disease.

[This corrects the article DOI: 10.3389/fncel.2021.

Striatal Chloride Dysregulation and Impaired GABAergic Signaling Due to Cation-Chloride Cotransporter Dysfunction in Huntington's Disease.

Intracellular chloride (Cl) levels in mature neurons must be tightly regulated for the maintenance of fast synaptic inhibition. In the mature central nervous system (CNS), synaptic inhibition is primarily mediated by gamma-amino butyric acid (GABA), which binds to Cl permeable GABA receptors (GABARs). The intracellular Cl concentration is primarily maintained by the antagonistic actions of two cation-chloride cotransporters (CCCs): Cl-importing Na-K-Cl co-transporter-1 (NKCC1) and Cl -exporting K-Cl co-transporter-2 (KCC2).

A Novel Small Molecule Targets NKCC1 To Restore Synaptic Inhibition.

Finely tuned excitation-inhibition balance is essential for proper brain function, and loss of balance resulting from reduced synaptic inhibition is associated with neurological disorders. Savardi and colleagues have discovered a novel inhibitor of a cation-chloride transporter that is required for synaptic inhibition, and which restores behaviors associated with Down syndrome (DS) and autism spectrum disorder (ASD).

Kainate receptor regulation of synaptic inhibition in the hippocampus.

Kainate receptors (KARs) are glutamate-type receptors that mediate both canonical ionotropic currents and non-canonical metabotropic signalling. While KARs are expressed widely throughout the brain, synaptic KAR currents have only been recorded at a limited set of synapses, and the KAR currents that have been recorded are relatively small and slow, which has led to the question, what is the functional significance of KARs? While the KAR current itself is relatively modest, its impact on inhibition in the hippocampus can be profound. In the CA1 region of the hippocampus, presynaptic KAR activation bidirectionally regulates γ-aminobutyric acid (GABA) release in a manner that depends on the glutamate concentration; lower levels of glutamate facilitate GABA release via an ionotropic pathway, while higher levels of glutamate depress GABA release via a metabotropic pathway.

Depolarizing GABA Transmission Restrains Activity-Dependent Glutamatergic Synapse Formation in the Developing Hippocampal Circuit.

γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mature brain but has the paradoxical property of depolarizing neurons during early development. Depolarization provided by GABA transmission during this early phase regulates neural stem cell proliferation, neural migration, neurite outgrowth, synapse formation, and circuit refinement, making GABA a key factor in neural circuit development. Importantly, depending on the context, depolarizing GABA transmission can either drive neural activity or inhibit it through shunting inhibition.

A field study to estimate inhalation rates for use in a particle inhalation rate exposure metric.

Particle inhalation rate (PIR) is an air pollution exposure metric that relies on age-, sex-, and physical activity-specific estimates of minute respiratory volume (MRV; L/min-kg) to account for personal inhalation patterns. United States Environmental Protection Agency (USEPA)-generated MRV estimates derive primarily from relatively homogenous populations without substantial cardiorespiratory challenges. To determine if these MRV estimates are relevant to populations in generally poor cardiorespiratory health (e.

Autism-Misregulated eIF4G Microexons Control Synaptic Translation and Higher Order Cognitive Functions.

Microexons represent the most highly conserved class of alternative splicing, yet their functions are poorly understood. Here, we focus on closely related neuronal microexons overlapping prion-like domains in the translation initiation factors, eIF4G1 and eIF4G3, the splicing of which is activity dependent and frequently disrupted in autism. CRISPR-Cas9 deletion of these microexons selectively upregulates synaptic proteins that control neuronal activity and plasticity and further triggers a gene expression program mirroring that of activated neurons.

Alterations in Hippocampal Inhibitory Synaptic Transmission in the R6/2 Mouse Model of Huntington's Disease.

Huntington's disease (HD) is a genetic neurodegenerative disorder of the central nervous system characterized by choreatic movements, behavioral and psychiatric disturbances and cognitive impairments. Deficits in learning and memory are often the first signs of disease onset in both HD patients and mouse models of HD and are in part regulated by the hippocampus. In the R6/2 mouse model of HD, GABAergic transmission can be excitatory in the hippocampus and restoring inhibition can rescue the associated memory deficits.

Ionotropic and metabotropic kainate receptor signalling regulates Cl homeostasis and GABAergic inhibition.

Key Points: Potassium-chloride co-transporter 2 (KCC2) plays a critical role in regulating chloride homeostasis, which is essential for hyperpolarizing inhibition in the mature nervous system. KCC2 interacts with many proteins involved in excitatory neurotransmission, including the GluK2 subunit of the kainate receptor (KAR). We show that activation of KARs hyperpolarizes the reversal potential for GABA (E ) via both ionotropic and metabotropic signalling mechanisms.

Relationship of Time-Activity-Adjusted Particle Number Concentration with Blood Pressure.

Emerging evidence suggests long-term exposure to ultrafine particulate matter (UFP, aerodynamic diameter < 0.1 µm) is associated with adverse cardiovascular outcomes. We investigated whether annual average UFP exposure was associated with measured systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and hypertension prevalence among 409 adults participating in the cross-sectional Community Assessment of Freeway Exposure and Health (CAFEH) study.

A Systematic Review and Meta-Analysis of the Association between Water, Sanitation, and Hygiene Exposures and Cholera in Case-Control Studies.

Case-control studies are conducted to identify cholera transmission routes. Water, sanitation, and hygiene (WASH) exposures can facilitate cholera transmission (risk factors) or interrupt transmission (protective factors). To our knowledge, the association between WASH exposures and cholera from case-control studies has not been systematically analyzed.

Longitudinal associations of long-term exposure to ultrafine particles with blood pressure and systemic inflammation in Puerto Rican adults.

Background: Few longitudinal studies have examined the association between ultrafine particulate matter (UFP, particles < 0.1 μm aerodynamic diameter) exposure and cardiovascular disease (CVD) risk factors. We used data from 791 adults participating in the longitudinal Boston Puerto Rican Health Study (Massachusetts, USA) between 2004 and 2015 to assess whether UFP exposure was associated with blood pressure and high sensitivity C-reactive protein (hsCRP, a biomarker of systemic inflammation).

Emerging Mechanisms Underlying Dynamics of GABAergic Synapses.

Inhibitory circuits are diverse, yet with a poorly understood cell biology. Functional characterization of distinct inhibitory neuron subtypes has not been sufficient to explain how GABAergic neurotransmission sculpts principal cell activity in a relevant fashion. Our Mini-Symposium brings together several emerging mechanisms that modulate GABAergic neurotransmission dynamically from either the presynaptic or the postsynaptic site.

Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition.

KCC2 is a neuron-specific K-Cl cotransporter essential for establishing the Cl gradient required for hyperpolarizing inhibition in the central nervous system (CNS). KCC2 is highly localized to excitatory synapses where it regulates spine morphogenesis and AMPA receptor confinement. Aberrant KCC2 function contributes to human neurological disorders including epilepsy and neuropathic pain.

Association of Long-Term Near-Highway Exposure to Ultrafine Particles with Cardiovascular Diseases, Diabetes and Hypertension.

Ultrafine particle (UFP) concentrations are elevated near busy roadways, however, their effects on prevalence of cardiovascular diseases, diabetes, and hypertension are not well understood. To investigate these associations, data on demographics, diseases, medication use, and time of activities were collected by in-home surveys for 704 participants in three pairs of near-highway and urban background neighborhoods in and near Boston (MA, USA). Body mass index (BMI) was measured for a subset of 435 participants.

A kainate receptor subunit promotes the recycling of the neuron-specific K-Cl co-transporter KCC2 in hippocampal neurons.

Synaptic inhibition depends on a transmembrane gradient of chloride, which is set by the neuron-specific K-Cl co-transporter KCC2. Reduced KCC2 levels in the neuronal membrane contribute to the generation of epilepsy, neuropathic pain, and autism spectrum disorders; thus, it is important to characterize the mechanisms regulating KCC2 expression. In the present study, we determined the role of KCC2-protein interactions in regulating total and surface membrane KCC2 expression.