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Edema is an important target for clinical intervention after traumatic brain injury (TBI). We used in vivo cellular resolution imaging and electrophysiological recording to examine the ionic mechanisms underlying neuronal edema and their effects on neuronal and network excitability after controlled cortical impact (CCI) in mice. Unexpectedly, we found that neuronal edema 48 hours after CCI was associated with reduced cellular and network excitability, concurrent with an increase in the expression ratio of the cation-chloride cotransporters (CCCs) NKCC1 and KCC2. Treatment with the CCC blocker bumetanide prevented neuronal swelling via a reversal in the NKCC1/KCC2 expression ratio, identifying altered chloride flux as the mechanism of neuronal edema. Importantly, bumetanide treatment was associated with increased neuronal and network excitability after injury, including increased susceptibility to spreading depolarizations (SDs) and seizures, known agents of clinical worsening after TBI. Treatment with mannitol, a first-line edema treatment in clinical practice, was also associated with increased susceptibility to SDs and seizures after CCI, showing that neuronal volume reduction, regardless of mechanism, was associated with an excitability increase. Finally, we observed an increase in excitability when neuronal edema normalized by 1 week after CCI. We conclude that neuronal swelling may exert protective effects against damaging excitability in the aftermath of TBI and that treatment of edema has the potential to reverse these effects., Introduction Traumatic brain injury (TBI) is a major cause of death and morbidity in both military and civilian populations (1). Because of the high incidence and the disability associated with [...]

Neurosteroids are synthesized within the brain and act as endogenous anxiolytic, anticonvulsant, hypnotic, and sedative agents, actions that are principally mediated via their ability to potentiate phasic and tonic inhibitory neurotransmission mediated by γ-aminobutyric acid type A receptors (GABAARs). Although neurosteroids are accepted allosteric modulators of GABAARs, here we reveal they exert sustained effects on GABAergic inhibition by selectively enhancing the trafficking of GABAARs that mediate tonic inhibition. We demonstrate that neurosteroids potentiate the protein kinase C-dependent phosphorylation of S443 within a4 subunits, a component of GABAAR subtypes that mediate tonic inhibition in many brain regions. This process enhances insertion of α4 subunit- containing GABAAR subtypes into the membrane, resulting in a selective and sustained elevation in the efficacy of tonic inhibition. Therefore, the ability of neurosteroids to modulate the phosphorylation and membrane insertion of α4 subunit-containing GABAARs may underlie the profound effects these endogenous signaling molecules have on neuronal excitability and behavior. [ABSTRACT FROM AUTHOR]

Disturbances of neuronal excitability changes during the ovarian cycle may elevate seizure frequency in women with catamenial epilepsy and enhance anxiety in premenstrual dysphoric disorder (PMDD). The mechanisms underlying these changes are unknown, but they could result from the effects of fluctuations in progesterone-derived neurosteroids on the brain. Neurosteroids and some anxiolytics share an important site of action: tonic inhibition mediated bydsubunit-containing GABAA receptors (dGABAARs). Here we demonstrate periodic alterations in specific GABAAR subunits during the estrous cycle in mice, causing cyclic changes of tonic inhibition in hippocampal neurons. In late diestrus (high-progesterone phase), enhanced expression ofdGABAARs increases tonic inhibition, and a reduced neuronal excitability is reflected by diminished seizure susceptibility and anxiety. Eliminating cycling ofdGABAARs by antisense RNA treatment or gene knockout prevents the lowering of excitability during diestrus. Our findings are consistent with possible deficiencies in regulatory mechanisms controlling normal cycling ofdGABAARs in individuals with catamenial epilepsy or PMDD. [ABSTRACT FROM AUTHOR]

Accumulating evidence supports a role for altered circuit function in impaired valence processing and altered affective states as a core feature of psychiatric illnesses. We review the circuit mechanisms underlying normal valence processing and highlight evidence supporting altered function of the basolateral amygdala (BLA), valence processing and affective states across psychiatric illnesses. The mechanisms controlling network activity which governs valence processing will be reviewed in the context of potential pathophysiological mechanisms mediating circuit dysfunction and impaired valence processing in psychiatric illnesses. Finally, we review emerging data demonstrating experience-dependent, biased information routing through the BLA promoting negative valence processing and discuss the potential relevance to impaired affective states and psychiatric illnesses., (Copyright © 2024. Published by Elsevier Inc.)

All current drug treatments for epilepsy, a neurological disorder affecting over 50 million people 1,2 merely treat symptoms, and a third of patients do not respond to medication. There are no disease modifying treatments that may be administered briefly to patients to enduringly eliminate spontaneous seizures and reverse cognitive deficits 3,4 . Applying network and systems-based approaches to rodent models and human temporal lobectomy samples, we observe the well-characterized pattern of rapid induction and subsequent quenching exhibited by the JAK/STAT pathway within days of epileptic insult. This is followed by an utterly unexpected, resurgent activation months later with the onset of spontaneous seizures. Targeting the first wave of activation after epileptic insult does not prevent disease. However, brief inhibition of the second wave with CP690550 (Tofacitinib) 5,6 enduringly suppresses seizures, rescues deficits in spatial memory, and restores neuropathological alterations to naïve levels. Seizure suppression lasts for at least 2 months after last dose. Using discovery-based transcriptomic analysis across models of epilepsy and validation of putative mechanisms with human data, we demonstrate a powerful approach to identifying disease modifying targets; this may be useful for other neurodegenerative diseases. With this approach, we find that reignition of inflammatory JAK/STAT3 signaling in chronic epilepsy opens a powerful window for disease modification with the FDA-approved, orally available drug CP690550.

Neurosteroids are synthesized within the brain and act as endogenous anxiolytic, anticonvulsant, hypnotic, and sedative agents, actions that are principally mediated via their ability to potentiate phasic and tonic inhibitory neurotransmission mediated by γ-aminobutyric acid type A receptors (GABAARs). Although neurosteroids are accepted allosteric modulators of GABAARs, here we reveal they exert sustained effects on GABAergic inhibition by selectively enhancing the trafficking of GABAARs that mediate tonic inhibition. We demonstrate that neurosteroids potentiate the protein kinase C-dependent phosphorylation of S443 within α4 subunits, a component of GABAAR subtypes that mediate tonic inhibition in many brain regions. This process enhances insertion of α4 subunit-containing GABAAR subtypes into the membrane, resulting in a selective and sustained elevation in the efficacy of tonic inhibition. Therefore, the ability of neurosteroids to modulate the phosphorylation and membrane insertion of α4 subunit-containing GABAARs may underlie the profound effects these endogenous signaling molecules have on neuronal excitability and behavior.

Loss of the astrocyte-specific intermediate filament protein, glial fibrillary acidic protein (GFAP) results in an increased susceptibility to ischemic insult, enhanced hippocampal LTP, and decreased cerebellar long-term depression (LTD). Because glutamate receptor activation plays a key role in cell death and cellular plasticity responses, we wanted to determine if alterations in glial glutamate transport could contribute to the GFAP null phenotype. To address functional changes in glutamate transport, we measured glutamate uptake in cortical, cerebellar, and hippocampal synaptosomal preparations from age-matched adult wild type and GFAP null mice and demonstrated a 25-30% reduction in the V(max) for d-aspartate uptake in the cortex and hippocampus of GFAP null animals. Western blot analysis of cortical synaptosomal fractions from wild type and GFAP null animals demonstrated that loss of GFAP results in decreases in both astrocytic (EAAT1) and neuronal (EAAT3) glutamate transporter subtypes. Immunohistochemical analysis demonstrated a region-specific modification of neuronal glutamate transporter, EAAT3 trafficking in the GFAP null phenotype. Analysis of primary cortical astrocyte cultures prepared from GFAP null and wild type mice demonstrated that loss of GFAP results in an inability to traffic the glial glutamate transporter, EAAT2, to the surface of the cell following protein kinase A (PKA) stimulation by dibutyryl cAMP. Taken together, these results suggest that the intermediate filament protein, GFAP plays a key role in modulating astrocytic and neuronal glutamate transporter trafficking and function.