Biology subjects

Jang, S.-S.

Publications and source records attributed to Jang, S.-S..

4 recordsLinked to original sources

bioRxiv2025

Reticular Thalamic Hyperexcitability Drives Autism Spectrum Disorder Behaviors in the Cntnap2 Model of Autism

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders characterized by social communication deficits, repetitive behaviors, and comorbidities such as sensory abnormalities, sleep disturbances, and seizures. Dysregulation of thalamocortical circuits has been implicated in these comorbid features, yet their precise roles in ASD pathophysiology remain elusive. This study focuses on the reticular thalamic nucleus (RT), a key regulator of thalamocortical interactions, to elucidate its contribution to ASD-related behavioral deficits using a Cntnap2 knockout (KO) mouse model. Our behavioral and EEG analyses comparing Cntnap2+/+ and Cntnap2-/- mice demonstrated that Cntnap2 knockout heightened seizure susceptibility, elevated locomotor activity, and produced hallmark ASD phenotypes, including social deficits, and repetitive behaviors. Electrophysiological recordings from thalamic brain slices revealed increased spontaneous and evoked network oscillations with increased RT excitability due to enhanced T-type calcium currents and burst firing. We observed behavior related heightened RT population activity in vivo with fiber photometry. Notably, suppressing RT activity via Z944, a T-type calcium channel blocker, and via C21 and the inhibitory DREADD hM4Di, improved ASD-related behavioral deficits. These findings identify RT hyperexcitability as a mechanistic driver of ASD behaviors and underscore RT as a potential therapeutic target for modulating thalamocortical circuit dysfunction in ASD. TeaserRT hyperexcitability drives ASD behaviors in Cntnap2-/- mice, highlighting RT as a therapeutic target for circuit dysfunction.

neuroscience↗

bioRxiv2025

Actions of the Anti-Seizure Drug Carbamazepine in the Thalamic Reticular Nucleus: Potential Mechanism of Aggravating Absence Seizures

Carbamazepine (CBZ) is a widely used antiepileptic drug effective in managing partial and generalized tonic-clonic seizures. Despite its established therapeutic efficacy, CBZ has been reported to worsen seizures in another form of epilepsy, generalized absence seizures, in both clinical and experimental settings. In this study, we focused on thalamic reticular (RT) neurons, which regulate thalamocortical network activity in absence seizures, to investigate whether CBZ alters their excitability, thereby contributing to the exacerbation of seizures. Using ex vivo whole-cell patch-clamp electrophysiology, we found that CBZ selectively inhibits the tonic firing of RT neurons in a dose-dependent manner without affecting burst firing. At the RT-thalamocortical (RT-TC) synapse, CBZ significantly increases the failure rate of GABAergic synaptic transmission, with greater effects on somatostatin (SST) - than parvalbumin (PV) - expressing RT neurons. In vivo EEG recordings and open-field behavior in Scn8amed+/- mouse model confirmed that CBZ treatment exacerbates absence seizures, increasing both seizure frequency and duration while reducing locomotor activity. In addition, CBZ further amplifies the pre-existing reduction in tonic firing of RT in Scn8amed+/- mice. These findings uncover a novel mechanism by which CBZ exacerbates absence seizures through selective inhibition of RT neuron excitability and disruption of GABAergic synaptic transmission. This work provides mechanistic insights into the paradoxical effects of CBZ and suggest potential avenues for optimizing epilepsy treatment strategies. Scientific SignificanceThis study addresses the clinical paradox in which CBZ, a widely prescribed antiepileptic drug, paradoxically aggravates absence seizures. Understanding the cellular mechanisms behind this phenomenon is critical for improving epilepsy treatments. Here, using electrophysiology recordings from intact thalamocortical slices and SCN8amed+/- mice, an absence seizure animal model, we demonstrate that CBZ selectively inhibits tonic firing of RT neurons and their output to thalamocortical circuits, with a more pronounced effect in SCN8amed+/- mice. These novel findings provide a mechanistic explanation for CBZs paradoxical aggravation of absence seizures, offering a framework for understanding the pharmacological effects of other anti-epilepsy drugs and guiding the development of more effective therapeutic strategies for epilepsy.

physiology↗

bioRxiv2023

Neuronal apoE4 induces early hyperexcitability in select populations of hippocampal neurons by altering Nell2 expression

The full impact of apolipoprotein E4 (APOE4), the strongest genetic risk factor for Alzheimers disease (AD), on neuronal and network function remains unclear. We found hippocampal region-specific network hyperexcitability in young APOE4 knock-in (E4-KI) mice which predicted cognitive deficits at old age. Network hyperexcitability in young E4-KI mice was mediated by hippocampal region-specific subpopulations of smaller and hyperexcitable neurons that were eliminated by selective removal of neuronal APOE4. Aged E4-KI mice exhibited hyperexcitable granule cells, a progressive inhibitory deficit, and E/I imbalance in the dentate gyrus, exacerbating hippocampal hyperexcitability. Single-nucleus RNA-sequencing revealed neuronal cell type-specific and age-dependent transcriptomic changes, including Nell2 overexpression in E4-KI mice. Reducing Nell2 expression in specific neuronal types of E4-KI mice with CRISPRi rescued their abnormal excitability phenotypes, implicating Nell2 overexpression as a cause of APOE4-induced hyperexcitability. These findings highlight the early transcriptomic and electrophysiological alterations underlying APOE4-induced hippocampal network dysfunction and its contribution to AD pathogenesis with aging.

neuroscience↗

bioRxiv2020

Aβ-induced NOX2 activation underlies oxidative stress leading to brain hypometabolism and hyperactivity in Alzheimer's disease

A predominant trigger and driver of sporadic Alzheimers disease (AD) is the synergy of brain oxidative stress and glucose hypometabolism starting at early preclinical stages. Oxidative stress damages macromolecules, while glucose hypometabolism impairs cellular energy supply and antioxidant defense. However, the exact cause of AD-associated glucose hypometabolism and its network consequences has remained unknown. Here we report NADPH oxidase 2 (NOX2) activation as the main initiating mechanism behind A{beta}1-42-related glucose hypometabolism and network dysfunction. We utilize a combination of electrophysiology with real-time recordings of metabolic transients both ex- and in-vivo to show that A{beta}1-42 induces oxidative stress and acutely reduces cellular glucose consumption followed by long-lasting network hyperactivity and abnormalities in the animal behavioral profile. Critically, all of these pathological changes were prevented by the novel bioavailable NOX2 antagonist GSK2795039. Our data provide the first direct experimental evidence for causes and consequences of AD-related brain glucose hypometabolism, and suggest that targeting NOX2-mediated oxidative stress is a promising approach to both the prevention and treatment of AD. Single sentence summaryBeta-amyloid induces brain hypometabolism, network hyperactivity, and behavioral changes via NADPH oxidase-mediated oxidative stress, suggesting a novel therapeutic target for Alzheimers disease treatment.

neuroscience↗