hyperexcitability

Stress deceleration theory: chronic adolescent stress exposure results in decelerated neurobehavioral maturation

Normative development in adolescence indicates that the prefrontal cortex is still under development thereby unable to exert efficient top-down inhibitory control on subcortical regions such as the basolateral amygdala and the nucleus accumbens. This imbalance in the developmental trajectory between cortical and subcortical regions is implicated in expression of the prototypical impulsive, compulsive, reward seeking and risk-taking adolescent behavior. Here we demonstrate that a chronic mild unpredictable stress procedure during adolescence in male Wistar rats arrests the normal behavioral maturation such that they continue to express adolescent-like impulsive, hyperactive, and compulsive behaviors into late adulthood. This arrest in behavioral maturation is associated with the hypoexcitability of prelimbic cortex (PLC) pyramidal neurons and reduced PLC-mediated synaptic glutamatergic control of BLA and nucleus accumbens core (NAcC) neurons that lasts late into adulthood. At the same time stress exposure in adolescence results in the hyperexcitability of the BLA pyramidal neurons sending stronger glutamatergic projections to the NAcC. Chemogenetic reversal of the PLC hypoexcitability decreased compulsivity and improved the expression of goal-directed behavior in rats exposed to stress during adolescence, suggesting a causal role for PLC hypoexcitability in this stress-induced arrested behavioral development. (https://www.biorxiv.org/content/10.1101/2021.11.21.469381v1.abstract)

Digging Deep: Uncovering Hidden Connections Between Epilepsy and Alzheimer’s Disease

An emerging hypothesis in the field of Alzheimer’s disease (AD) is that neuronal hyperexcitability and other forms of aberrant network activity play an important role in shaping the clinical course of AD. In this talk, Dr. Lam will highlight the close and bi-directional relationships between epilepsy and AD, noting recent advances in our understanding of this topic spanning from animal models to humans. She will describe recent intracranial electrode recordings in humans that have revealed silent hippocampal epileptiform activity occurring in early stages of AD. Finally, she will discuss machine learning approaches that her laboratory has been developing to non-invasively diagnose and quantify silent hippocampal epileptiform activity from scalp EEG recordings.

Playing fast and loose with glutamate builds healthy circuits in the developing cortex

The construction of cortical circuits requires the precise formation of connections between excitatory and inhibitory neurons during early development. Multiple factors, including neurotransmitters, neuronal activity, and neuronal-glial interactions, shape how these critical circuits form. Disruptions of these early processes can disrupt circuit formation, leading to epilepsy and other neurodevelopmental disorders. Here, I will describe our work into understanding how prolonged post-natal astrocyte development in the cortex creates a permissive window for glutamate signaling that provides tonic activation of developing interneurons through Grin2D NMDA receptors. Experimental disruption of this pathway results in hyperexcitable cortical circuits and human mutations in the Grin2D gene, as well as other related molecules that regulate early life glutamate signaling, are associated with devastating epileptic encephalopathies. We will explore fundamental mechanisms linking early life glutamate signaling and later circuit hyperexcitability, with an emphasis on potential therapeutic interventions aimed at reducing epilepsy and other neurological dysfunction.

K+ Channel Gain of Function in Epilepsy, from Currents to Networks

Recent human gene discovery efforts show that gain-of-function (GOF) variants in the KCNT1gene, which encodes a Na+-activated K+ channel subunit, cause severe epilepsies and other neurodevelopmental disorders. Although the impact of these variants on the biophysical properties of the channels is well characterized, the mechanisms that link channel dysfunction to cellular and network hyperexcitability and human disease are unknown. Furthermore, precision therapies that correct channel biophysics in non-neuronal cells have had limited success in treating human disease, highlighting the need for a deeper understanding of how these variants affect neurons and networks. To address this gap, we developed a new mouse model with a pathogenic human variant knocked into the mouse Kcnt1gene. I will discuss our findings on the in vivo phenotypes of this mouse, focusing on our characterization of epileptiform neural activity using electrophysiology and widefield Ca++imaging. I will also talk about our investigations at the synaptic, cellular, and circuit levels, including the main finding that cortical inhibitory neurons in this model show a reduction in intrinsic excitability and action potential generation. Finally, I will discuss future directions to better understand the mechanisms underlying the cell-type specific effects, as well as the link between the cellular and network level effects of KCNT1 GOF.

Sparks, flames, and inferno: epileptogenesis in the glioblastoma microenvironment

Glioblastoma cells trigger pharmacoresistant seizures that may promote tumor growth and diminish the quality of remaining life. To define the relationship between growth of glial tumors and their neuronal microenvironment, and to identify genomic biomarkers and mechanisms that may point to better prognosis and treatment of drug resistant epilepsy in brain cancer, we are analyzing a new generation of genetically defined CRISPR/in utero electroporation inborn glioblastoma (GBM) tumor models engineered in mice. The molecular pathophysiology of glioblastoma cells and surrounding neurons and untransformed astrocytes are compared at serial stages of tumor development. Initial studies reveal that epileptiform EEG spiking is a very early and reliable preclinical signature of GBM expansion in these mice, followed by rapidly progressive seizures and death within weeks. FACS-sorted transcriptomic analysis of cortical astrocytes reveals the expansion of a subgroup enriched in pro-synaptogenic genes that may drive hyperexcitability, a novel mechanism of epileptogenesis. Using a prototypical GBM IUE model, we systematically define and correlate the earliest appearance of cortical hyperexcitability with progressive cortical tumor cell invasion, including spontaneous episodes of spreading cortical depolarization, innate inflammation, and xCT upregulation in the peritumoral microenvironment. Blocking this glutamate exporter reduces seizure load. We show that the host genome contributes to seizure risk by generating tumors in a monogenic deletion strain (MapT/tau -/-) that raises cortical seizure threshold. We also show that the tumor variant profile determines epilepsy risk. Our genetic dissection approach sets the stage to broadly explore the developmental biology of personalized tumor/host interactions in mice engineered with novel human tumor mutations in specified glial cell lineages.

Cellular/circuit dysfunction in a model of Dravet syndrome - a severe childhood epilepsy

Dravet syndrome is a severe childhood epilepsy due to heterozygous loss-of-function mutation of the gene SCN1A, which encodes the type 1 neuronal voltage gated sodium (Na+) channel alpha-subunit Nav1.1. Prior studies in mouse models of Dravet syndrome (Scn1a+/- mice) at early developmental time points indicate that, in cerebral cortex, Nav1.1 is predominantly expressed in GABAergic interneurons (INs) and, in particular, in parvalbumin-positive fast-spiking basket cells (PV-INs). This has led to a model of Dravet syndrome pathogenesis whereby Nav1.1 mutation leads to preferential IN dysfunction, decreased synaptic inhibition, hyperexcitability, and epilepsy. We found that, at later developmental time points, the intrinsic excitability of PV-INs has essentially normalized, via compensatory reorganization of axonal Na+ channels. Instead, we found persistent and seemingly paradoxical dysfunction of putative disinhibitory INs expressing vasoactive intestinal peptide (VIP-INs). In vivo two-photon calcium imaging in neocortex during temperature-induced seizures in Scn1a+/- mice showed that mean activity of both putative principal cells and PV-INs was higher in Scn1a+/- relative to wild-type controls during quiet wakefulness at baseline and at elevated core body temperature. However, wild-type PV-INs showed a progressive synchronization in response to temperature elevation that was absent in PV-INs from Scn1a+/- mice immediately prior to seizure onset. We suggest that impaired PV-IN synchronization, perhaps via persistent axonal dysfunction, may contribute to the transition to the ictal state during temperature induced seizures in Dravet syndrome.

ASTROCYTE-DRIVEN HYPEREXCITABILITY AS A THERAPEUTIC TARGET IN EPILEPSY

FENS Forum 2026

ALTERED AMPA RECEPTOR SUBUNIT CONFIGURATION DRIVES HYPEREXCITABILITY IN BCNU MODEL OF FOCAL CORTICAL DYSPLASIA (FCD)

FENS Forum 2026

AUTAPTIC SELF-INHIBITION OF PARVALBUMIN INTERNEURONS DRIVES NETWORK HYPEREXCITABILITY IN GABAA RECEPTOR GAIN-OF-FUNCTION ENCEPHALOPATHY

FENS Forum 2026

HUMAN CORTICAL BRAIN ORGANOIDS EXPRESSING P301L TAU REVEAL EARLY TAU-DRIVEN NETWORK HYPEREXCITABILITY IN FTDP-17

FENS Forum 2026

TDP-43 PATHOLOGY DRIVES MOTONEURONE HYPEREXCITABILITY IN A CELL-AUTONOMOUS MANNER

FENS Forum 2026

DECIPHERING THE MECHANISMS UNDERLYING AUDITORY HYPEREXCITABILITY IN TWO GENETIC MOUSE MODELS SUSCEPTIBLE TO AUDIOGENIC SEIZURES

FENS Forum 2026

ATF3 PROMOTES INTRINSIC DRG NEURON HYPEREXCITABILITY AND NEUROMA PAIN AFTER TRANSECTION

FENS Forum 2026

HIPPOCAMPAL DG HYPEREXCITABILITY IN IPSC-DERIVED NEURONS FROM BD PATIENTS STRATIFIED BY SUICIDE OUTCOME

FENS Forum 2026

DYSREGULATION OF JANUS KINASE- AND MICROTUBULE-INTERACTING PROTEIN 1 (JAKMIP1) IS ASSOCIATED WITH ALTERED STAT3 SIGNALLING, SOMATOSENSORY CORTICAL HYPEREXCITABILITY, AND AUTISM-LIKE BEHAVIOURS

FENS Forum 2026

LAYER-SPECIFIC AXON INITIAL SEGMENT PLASTICITY UNDERLIES CORTICAL HYPEREXCITABILITY IN TRIGEMINAL PAIN

FENS Forum 2026

<EM>FMR1 </EM>REDUCTION DRIVES CELL-TYPE TRANSCRIPTOMIC REMODELING AND HYPEREXCITABILITY IN HUMAN CORTICAL CIRCUITS

FENS Forum 2026

NITROUS OXIDE ALLEVIATES STRESS AND MODULATES CENTRAL AMYGDALA HYPEREXCITABILITY

FENS Forum 2026

MODULATION OF CHOLESTEROL METABOLISM AMELIORATES NEURONAL HYPEREXCITABILITY AND NEUROINFLAMMATION IN A <EM>GRIN2D</EM>-RELATED DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY MODEL

FENS Forum 2026

EMERGING PATTERNS OF ASTROGLIA-NEURON INTERACTIONS IN NETWORK HYPEREXCITABILITY AND SEIZURES

FENS Forum 2026

ELEVATED ASTROCYTIC GAT3 LINKS TO NEURONAL HYPEREXCITABILITY IN A HUMAN IPSC DERIVED ALZHEIMER’S TRICULTURE MODEL

FENS Forum 2026

Neonatal CA3 hyperexcitability drives hippocampal epileptogenesis in SCN2A epileptic encephalopathy

FENS Forum 2024

A pH-sensitive closed-loop nanomachine to control hyperexcitability at the single neuron level

FENS Forum 2024

The role of astroglial homeostatic functioning and astroglia-neuron interactions in network hyperexcitability

FENS Forum 2024

Microcircuit failure in STXBP1 encephalopathy leads to hyperexcitability

FENS Forum 2024

Decreased noradrenaline levels contribute to cortical hyperexcitability in mouse models of amyotrophic lateral sclerosis

The genetic downregulation of calpain 1 reverts spinal hyperexcitability in a neonate mouse model of complete spinal cord injury

CA1 hyperexcitability drives anesthesia-induced early memory dysfunctions in Alzheimer’s model mice

Hyperexcitability and Wnt/β-catenin signaling pathway in neurons derived from bipolar disorder patients

A Kv3.3 voltage-gated potassium channel mutation induces presynaptic hyperexcitability and raises the number of docked vesicles at hippocampal excitatory synapses

PTK2B regulates electrical activity in human neurons and plays a role in the Aβ1-42-mediated neuronal hyperexcitability

SST-positive GABAergic interneurons counterbalance cortical hyperexcitability after traumatic brain injury in mice by a switch of α-subunits in L-type voltage-gated calcium channels

Anterior cingulate cortex hyperexcitability in a mouse model of attention-deficit/hyperactivity disorder and pain comorbidity

FENS Forum 2024

Deciphering the mechanisms underlying auditory hyperexcitability in a genetic mouse model susceptible to audiogenic seizures

FENS Forum 2024

Early hippocampal hyperexcitability and mitochondrial changes in a transgenic mouse model of dementia with Lewy bodies

FENS Forum 2024

Early maturation and hyperexcitability is a shared phenotype of cortical neurons derived from different ASD-associated mutations

FENS Forum 2024

Evidence of prodromal neuronal hyperexcitability and neuroinflammation in a rodent model of human alpha-synucleinopathy

FENS Forum 2024

Functional connectivity as biomarker for network hyperexcitability in Alzheimer’s disease

FENS Forum 2024

Assessing the hyperexcitability of the epileptic brain by burst-suppression EEG reactivity