Environmental exposure to common pesticide induces synaptic deficit and social memory impairment driven by neurodevelopmental vulnerability of hippocampal parvalbumin interneurons.

Environmental exposure to pesticides at levels deemed safe by regulatory agencies has been linked to increased risk for neurodevelopmental disorders. Yet, the mechanisms linking exposure to these disorders remain unclear. Here, we show that maternal exposure to the pesticide deltamethrin (DM) at the no observed adverse effect level (NOAEL) disrupts long-term potentiation (LTP) in the hippocampus of adult male offspring three months after exposure, a phenotype absent in female offspring.

Bar press durations as a reliable and robust measure of frustration-related operant behavior: Sensitivity to incentive downshift and dose-response paradigms.

In humans, frustrating experiences are known to trigger relapse events and individuals with higher frustration intolerance show increased risk of developing substance use disorders (SUDs). Despite this clear relationship, frustration-related behavior is seldom studied concurrently with self-administration behavior in rodent models. A major obstacle has been the lack of robust, quantitative assays of frustration-related operant behavior thus far.

TNFR1 signaling converging on FGF14 controls neuronal hyperactivity and sickness behavior in experimental cerebral malaria.

Background: Excess tumor necrosis factor (TNF) is implicated in the pathogenesis of hyperinflammatory experimental cerebral malaria (eCM), including gliosis, increased levels of fibrin(ogen) in the brain, behavioral changes, and mortality. However, the role of TNF in eCM within the brain parenchyma, particularly directly on neurons, remains underdefined. Here, we investigate electrophysiological consequences of eCM on neuronal excitability and cell signaling mechanisms that contribute to observed phenotypes.

Fibroblast growth factor 13-mediated regulation of medium spiny neuron excitability and cocaine self-administration.

Cocaine use disorder (CUD) is a prevalent neuropsychiatric disorder with few existing treatments. Thus, there is an unmet need for the identification of new pharmacological targets for CUD. Previous studies using environmental enrichment versus isolation paradigms have found that the latter induces increased cocaine self-administration with correlative increases in the excitability of medium spiny neurons (MSN) of the nucleus accumbens shell (NAcSh).

Voltage-Gated Na Channels in Alzheimer's Disease: Physiological Roles and Therapeutic Potential.

Alzheimer's disease (AD) is the most common cause of dementia and is classically characterized by two major histopathological abnormalities: extracellular plaques composed of amyloid beta (Aβ) and intracellular hyperphosphorylated tau. Due to the progressive nature of the disease, it is of the utmost importance to develop disease-modifying therapeutics that tackle AD pathology in its early stages. Attenuation of hippocampal hyperactivity, one of the earliest neuronal abnormalities observed in AD brains, has emerged as a promising strategy to ameliorate cognitive deficits and abate the spread of neurotoxic species.

Glycogen Synthase Kinase 3: Ion Channels, Plasticity, and Diseases.

Glycogen synthase kinase 3β (GSK3) is a multifaceted serine/threonine (S/T) kinase expressed in all eukaryotic cells. GSK3β is highly enriched in neurons in the central nervous system where it acts as a central hub for intracellular signaling downstream of receptors critical for neuronal function. Unlike other kinases, GSK3β is constitutively active, and its modulation mainly involves inhibition via upstream regulatory pathways rather than increased activation.

Inhibition of the Akt/PKB Kinase Increases Na1.6-Mediated Currents and Neuronal Excitability in CA1 Hippocampal Pyramidal Neurons.

In neurons, changes in Akt activity have been detected in response to the stimulation of transmembrane receptors. However, the mechanisms that lead to changes in neuronal function upon Akt inhibition are still poorly understood. In the present study, we interrogate how Akt inhibition could affect the activity of the neuronal Na channels with while impacting intrinsic excitability.

A Learning Based Framework for Disease Prediction from Images of Human-Derived Pluripotent Stem Cells of Schizophrenia Patients.

Human induced pluripotent stem cells (hiPSCs) have been employed very successfully to identify molecular and cellular features of psychiatric disorders that would be impossible to discover in traditional postmortem studies. Despite the wealth of new available information though, there is still a critical need to establish quantifiable and accessible molecular markers that can be used to reveal the biological causality of the disease. In this paper, we introduce a new quantitative framework based on supervised learning to investigate structural alterations in the neuronal cytoskeleton of hiPSCs of schizophrenia (SCZ) patients.

Pharmacologically Targeting the Fibroblast Growth Factor 14 Interaction Site on the Voltage-Gated Na Channel 1.6 Enables Isoform-Selective Modulation.

Voltage-gated Na (Na) channels are the primary molecular determinant of the action potential. Among the nine isoforms of the Na channel α subunit that have been described (Na1.1-Na1.

Pharmacological Inhibition of Wee1 Kinase Selectively Modulates the Voltage-Gated Na Channel 1.2 Macromolecular Complex.

Voltage-gated Na (Na) channels are a primary molecular determinant of the action potential (AP). Despite the canonical role of the pore-forming α subunit in conferring this function, protein-protein interactions (PPI) between the Na channel α subunit and its auxiliary proteins are necessary to reconstitute the full physiological activity of the channel and to fine-tune neuronal excitability. In the brain, the Na channel isoforms 1.

Individual Differences in Frustrative Nonreward Behavior for Sucrose in Rats Predict Motivation for Fentanyl under Progressive Ratio.

Frustrative nonreward (FN) is a construct in the Negative Valence Systems domain of the Research Domain Criteria (RDoC) from the National Institute of Mental Health. An organism's response to frustrating situations (e.g.

Differential Modulation of the Voltage-Gated Na Channel 1.6 by Peptides Derived From Fibroblast Growth Factor 14.

The voltage-gated Na (Nav) channel is a primary molecular determinant of the initiation and propagation of the action potential. Despite the central role of the pore-forming α subunit in conferring this functionality, protein:protein interactions (PPI) between the α subunit and auxiliary proteins are necessary for the full physiological activity of Nav channels. In the central nervous system (CNS), one such PPI occurs between the C-terminal domain of the Nav1.

Inhibition of AKT Signaling Alters βIV Spectrin Distribution at the AIS and Increases Neuronal Excitability.

The axon initial segment (AIS) is a highly regulated subcellular domain required for neuronal firing. Changes in the AIS protein composition and distribution are a form of structural plasticity, which powerfully regulates neuronal activity and may underlie several neuropsychiatric and neurodegenerative disorders. Despite its physiological and pathophysiological relevance, the signaling pathways mediating AIS protein distribution are still poorly studied.

Development of Allosteric Modulators of Voltage-Gated Na Channels: A Novel Approach for an Old Target.

Given their primacy in governing the action potential (AP) of excitable cells, voltage-gated Na+ (Nav) channels are important pharmacological targets of therapeutics for a diverse array of clinical indications. Despite historically being a traditional drug target, therapeutics targeting Nav channels lack isoform selectivity, giving rise to off-target side effects. To develop isoform-selective modulators of Nav channels with improved target-specificity, the identification and pharmacological targeting of allosteric sites that display structural divergence among Nav channel isoforms represents an attractive approach.

Convergent genomic and pharmacological evidence of PI3K/GSK3 signaling alterations in neurons from schizophrenia patients.

Human-induced pluripotent stem cells (hiPSCs) allow for the establishment of brain cellular models of psychiatric disorders that account for a patient's genetic background. Here, we conducted an RNA-sequencing profiling study of hiPSC-derived cell lines from schizophrenia (SCZ) subjects, most of which are from a multiplex family, from the population isolate of the Central Valley of Costa Rica. hiPSCs, neural precursor cells, and cortical neurons derived from six healthy controls and seven SCZ subjects were generated using standard methodology.

Topographic transcriptomics of the nucleus accumbens shell: Identification and validation of fatty acid binding protein 5 as target for cocaine addiction.

Substance use disorders for cocaine are major public health concerns with few effective treatment options. Therefore, identification of novel pharmacotherapeutic targets is critical for future therapeutic development. Evolution has ensured that genes are expressed largely only where they are needed.

Bioluminescence Methodology for Ion Channel Studies.

As key players in cell function, ion channels are important targets for drug discovery and therapeutic development against a wide range of health conditions. Thus, developing assays to reconstitute ion channel macromolecular complexes in physiological conditions and screen for chemical modifiers of protein-protein interactions within these complexes is timely in drug discovery campaigns. For most ion channels, expressing their pore-forming subunit in heterologous mammalian cells has now become a routine procedure.

Design, Synthesis, and Pharmacological Evaluation of Analogues Derived from the PLEV Tetrapeptide as Protein-Protein Interaction Modulators of Voltage-Gated Sodium Channel 1.6.

The voltage-gated Na (Na) channel is the molecular determinant of excitability. Disruption of protein-protein interactions (PPIs) between Na1.6 and fibroblast growth factor 14 (FGF14) leads to impaired excitability of neurons in clinically relevant brain areas associated with channelopathies.

Bidirectional Modulation of the Voltage-Gated Sodium (Nav1.6) Channel by Rationally Designed Peptidomimetics.

Disruption of protein:protein interactions (PPIs) that regulate the function of voltage-gated Na (Nav) channels leads to neural circuitry aberrations that have been implicated in numerous channelopathies. One example of this pathophysiology is mediated by dysfunction of the PPI between Nav1.6 and its regulatory protein fibroblast growth factor 14 (FGF14).

Mapping of the FGF14:Nav1.6 complex interface reveals FLPK as a functionally active peptide modulating excitability.

The voltage-gated sodium (Nav) channel complex is comprised of pore-forming α subunits (Nav1.1-1.9) and accessory regulatory proteins such as the intracellular fibroblast growth factor 14 (FGF14).

JAK2 regulates Nav1.6 channel function via FGF14 phosphorylation.

Background: Protein interactions between voltage-gated sodium (Nav) channels and accessory proteins play an essential role in neuronal firing and plasticity. However, a surprisingly limited number of kinases have been identified as regulators of these molecular complexes. We hypothesized that numerous as-of-yet unidentified kinases indirectly regulate the Nav channel via modulation of the intracellular fibroblast growth factor 14 (FGF14), an accessory protein with numerous unexplored phosphomotifs and required for channel function in neurons.

Effects of Deltamethrin Acute Exposure on Nav1.6 Channels and Medium Spiny Neurons of the Nucleus Accumbens.

Exposure to pyrethroids, a popular insecticide class that targets voltage-gated Na+ (Nav) channels, has been correlated to an increase in diagnosis of neurodevelopmental disorders, such as attention deficit hyperactive disorder (ADHD), in children. Dysregulation of medium spiny neurons (MSNs) firing in the nucleus accumbens (NAc) is thought to play a critical role in the pathophysiology of ADHD and other neurodevelopmental disorders. The Nav1.

Chronic mild stress alters synaptic plasticity in the nucleus accumbens through GSK3β-dependent modulation of Kv4.2 channels.

Although major depressive disorder (MDD) is highly prevalent, its pathophysiology is poorly understood. Recent evidence suggests that glycogen-synthase kinase 3β (GSK3β) plays a key role in memory formation, yet its role in mood regulation remains controversial. Here, we investigated whether GSK3β activity in the nucleus accumbens (NAc) is associated with depression-like behaviors and synaptic plasticity.