Sinziana Avramescu

Memory Deficits Induced by Inflammation Are Regulated by α5-Subunit-Containing GABAA Receptors

SUMMARY Systemic inflammation causes learning and memory deficits through mechanisms that remain poorly understood. Here, we studied the pathogenesis of memory loss associated with inflammation and found that we could reverse memory deficits by pharmacologically inhibiting α5-subunit-containing γ-aminobutyric acid type A (α5GABAA) receptors and deleting the gene associated with the α5 subunit. Acute inflammation reduces long-term potentiation, a synaptic correlate of memory, in hippocampal slices from wild-type mice, and this reduction was reversed by inhibition of α5GABAA receptor function. A tonic inhibitory current generated by α5GABAA receptors in hippocampal neurons was increased by the key proinflammatory cytokine interleukin-1β through a p38 mitogen-activated protein kinase signaling pathway. Interleukin-1β also increased the surface expression of α5GABAA receptors in the hippocampus. Collectively, these results show that α5GABAA receptor activity increases during inflammation and that this increase is critical for inflammation-induced memory deficits.

Synaptic Strength Modulation after Cortical Trauma: A Role in Epileptogenesis

Traumatic brain injuries are often followed by abnormal hyperexcitability, leading to acute seizures and epilepsy. Previous studies documented the rewiring capacity of neocortical neurons in response to various cortical and subcortical lesions. However, little information is available on the functional consequences of these anatomical changes after cortical trauma and the adaptation of synaptic connectivity to a decreased input produced by chronic deafferentation. In this study, we recorded intracellular (IC) activities of cortical neurons simultaneously with extracellular (EC) unit activities and field potentials of neighboring cells in cat cortex, after a large transection of the white matter underneath the suprasylvian gyrus, in acute and chronic conditions (at 2, 4, and 6 weeks) in ketamine–xylazine-anesthetized cats. Using EC spikes to compute the spike-triggered averages of IC membrane potential, we found an increased connection probability and efficacy between cortical neurons weeks after cortical trauma. Inhibitory interactions showed no significant changes in the traumatized cortex compared with control. The increased synaptic efficacy was accompanied by enhanced input resistance and intrinsic excitability of cortical neurons, as well as by increased duration of silent network periods. Our electrophysiological data revealed functional consequences of previously reported anatomical changes in the injured cortex. We suggest that homeostatic synaptic plasticity compensating the decreased activity in the undercut cortex leads to an uncontrollable cortical hyperexcitability and seizure generation.

Posttraumatic Epilepsy: The Roles of Synaptic Plasticity:

Acute cerebral cortical trauma often leads to paroxysmal activities that terminate in a few hours, but several months later, patients can develop epilepsy. The process occurring between the initial acute triggered seizures and the onset of spontaneous unprovoked seizures is termed epileptogenesis. Here the authors summarize recent morphological, electrophysiological, and computational studies demonstrating that partial cortical isolation increases the number and duration of silent states in the cortical network, boosting neuronal connectivity and network excitability. These changes develop progressively, and after several weeks their synergetic action leads to epilepsy.

Tranexamic acid-associated seizures: Causes and treatment.

Antifibrinolytic drugs are routinely used worldwide to reduce the bleeding that results from a wide range of hemorrhagic conditions. The most commonly used antifibrinolytic drug, tranexamic acid, is associated with an increased incidence of postoperative seizures. The reported increase in the frequency of seizures is alarming, as these events are associated with adverse neurological outcomes, longer hospital stays, and increased in‐hospital mortality. However, many clinicians are unaware that tranexamic acid causes seizures. The goal of this review is to summarize the incidence, risk factors, and clinical features of these seizures. This review also highlights several clinical and preclinical studies that offer mechanistic insights into the potential causes of and treatments for tranexamic acid–associated seizures. This review will aid the medical community by increasing awareness about tranexamic acid–associated seizures and by translating scientific findings into therapeutic interventions for patients. ANN NEUROL 2016;79:18–26

Neocortical post-traumatic epileptogenesis is associated with loss of GABAergic neurons.

The subtle mechanisms of post-traumatic epileptogenesis remain unknown, although the incidence of chronic epilepsy after penetrating cortical wounds is high. Here, we investigated whether the increased frequency of seizures occurring within 6 weeks following partial deafferentation of the suprasylvian gyrus in cats is accompanied with a change in the ratio between the number of excitatory and inhibitory neurons. Immuno-histochemical labeling of all neurons with neuronal-specific nuclear protein (NeuN) antibody, and of the GABAergic inhibitory neurons with either gamma-aminobutyric acid (GABA) or glutamic acid decarboxylase (GAD 65&67) antibodies, was performed on sections obtained from control and epileptic animals with chronically deafferented suprasylvian gyrus. Quantification of the labeled neurons was performed in control animals and at 2, 4, and 6 weeks following cortical deafferentation, in the suprasylvian and marginal gyri, both ipsi- and contra-lateral to the cortical trauma. In all epileptic animals, the neuronal loss was circumscribed to the deafferented suprasylvian gyrus. Inhibitory GABAergic neurons were particularly more sensitive to cortical deafferentation than excitatory ones, leading to a progressively increasing ratio between excitation and inhibition towards excitation, potentially explaining the increased propensity to seizures in chronic undercut cortex.

Inflammation Increases Neuronal Sensitivity to General Anesthetics.

Background:Critically ill patients with severe inflammation often exhibit heightened sensitivity to general anesthetics; however, the underlying mechanisms remain poorly understood. Inflammation increases the number of &ggr;-aminobutyric acid type A (GABAA) receptors expressed on the surface of neurons, which supports the hypothesis that inflammation increases up-regulation of GABAA receptor activity by anesthetics, thereby enhancing the behavioral sensitivity to these drugs. Methods:To mimic inflammation in vitro, cultured hippocampal and cortical neurons were pretreated with interleukin (IL)-1&bgr;. Whole cell patch clamp methods were used to record currents evoked by &ggr;-aminobutyric acid (GABA) (0.5 &mgr;M) in the absence and presence of etomidate or isoflurane. To mimic inflammation in vivo, mice were treated with lipopolysaccharide, and several anesthetic-related behavioral endpoints were examined. Results:IL-1&bgr; increased the amplitude of current evoked by GABA in combination with clinically relevant concentrations of either etomidate (3 &mgr;M) or isoflurane (250 &mgr;M) (n = 5 to 17, P < 0.05). Concentration–response plots for etomidate and isoflurane showed that IL-1&bgr; increased the maximal current 3.3-fold (n = 5 to 9) and 1.5-fold (n = 8 to 11), respectively (P < 0.05 for both), whereas the half-maximal effective concentrations were unchanged. Lipopolysaccharide enhanced the hypnotic properties of both etomidate and isoflurane. The immobilizing properties of etomidate, but not isoflurane, were also increased by lipopolysaccharide. Both lipopolysaccharide and etomidate impaired contextual fear memory. Conclusions:These results provide proof-of-concept evidence that inflammation increases the sensitivity of neurons to general anesthetics. This increase in anesthetic up-regulation of GABAA receptor activity in vitro correlates with enhanced sensitivity for GABAA receptor–dependent behavioral endpoints in vivo.

Sonoanatomy of the thoracic spine in adult volunteers.

Background and Objectives Ultrasonography of the lumbar spine provides information to facilitate the placement of neuraxial anesthesia. Likewise, thoracic spine ultrasound (US) might conceivably improve the quality and safety of thoracic epidural anesthesia. The objective of this study was to advance our understanding in this area by providing a detailed description of the sonoanatomy of the thoracic spine. Methods This was a prospective, observational, cohort study in 61 adult volunteers. We performed US scanning of all thoracic interspaces in the right paramedian sagittal oblique (PSO) and transverse median (TM) planes. The images were classified as conclusive and inconclusive, depending on the visibility of ligamentum flavum–dura mater complex (Lf-Dm). The primary outcome was the presence of conclusive images. The secondary outcomes were measurements of various distances between sonoanatomic elements. Data are presented as mean (SD), unless otherwise specified. Results Overall, the incidence of conclusive images was higher in the PSO than in the TM plane (74.5% [15.4%] versus 37.5% [39.7%], P < 0.001). In the lower thoracic levels, 98% of images were conclusive in both planes, but the number of conclusive images decreased progressively in the upper thoracic levels, more so in the TM than in the PSO plane. The mean depth to Lf-Dm was similar when measured in both PSO (4.0 [0.7] cm) and TM planes (4.1 [0.7] cm). Conclusions Ultrasound imaging of the thoracic spine in the PSO plane provides better views of the Lf-Dm compared with the TM plane. A upper incidence of inconclusive sonograms should be expected in the upper thoracic segments, which can be attributed to the narrower acoustic windows at these levels.

Dexmedetomidine Prevents Excessive γ-Aminobutyric Acid Type A Receptor Function after Anesthesia

What We Already Know about This TopicDexmedetomidine is effective in reducing delirium in the postoperative period and in the intensive care unit in patients and prevents memory deficits in experimental animals subjected to anesthesia. The mechanism by which dexmedetomidine preserves cognition is not clear.In experimental models, even a single anesthetic exposure leads to a sustained increase in the expression of cell-surface &ggr;-aminobutyric acid type A receptors that contain &agr;5 subunits. Whether dexmedetomidine reduces this increase and preserves cognition was evaluated. What This Article Tells Us That Is NewDexmedetomidine, by an &agr;2 receptor-mediated release of brain-derived neurotrophic factor from astrocytes, reduced neuronal &agr;5 &ggr;-aminobutyric acid type A receptor expression and prevented cognitive deficits after anesthesia.The data suggest that suppression of anesthesia-induced sustained increase in &agr;5 &ggr;-aminobutyric acid type A receptor expression may be a potential therapeutic target for the prevention of postoperative and intensive care unit delirium. Background: Postoperative delirium is associated with poor long-term outcomes and increased mortality. General anesthetic drugs may contribute to delirium because they increase cell-surface expression and function of &agr;5 subunit-containing &ggr;-aminobutyric acid type A receptors, an effect that persists long after the drugs have been eliminated. Dexmedetomidine, an &agr;2 adrenergic receptor agonist, prevents delirium in patients and reduces cognitive deficits in animals. Thus, it was postulated that dexmedetomidine prevents excessive function of &agr;5 &ggr;-aminobutyric acid type A receptors. Methods: Injectable (etomidate) and inhaled (sevoflurane) anesthetic drugs were studied using cultured murine hippocampal neurons, cultured murine and human cortical astrocytes, and ex vivo murine hippocampal slices. &ggr;-Aminobutyric acid type A receptor function and cell-signaling pathways were studied using electrophysiologic and biochemical methods. Memory and problem-solving behaviors were also studied. Results: The etomidate-induced sustained increase in &agr;5 &ggr;-aminobutyric acid type A receptor cell-surface expression was reduced by dexmedetomidine (mean ± SD, etomidate: 146.4 ± 51.6% vs. etomidate + dexmedetomidine: 118.4 ± 39.1% of control, n = 8 each). Dexmedetomidine also reduced the persistent increase in tonic inhibitory current in hippocampal neurons (etomidate: 1.44 ± 0.33 pA/pF, n = 10; etomidate + dexmedetomidine: 1.01 ± 0.45 pA/pF, n = 9). Similarly, dexmedetomidine prevented a sevoflurane-induced increase in the tonic current. Dexmedetomidine stimulated astrocytes to release brain-derived neurotrophic factor, which acted as a paracrine factor to reduce excessive &agr;5 &ggr;-aminobutyric acid type A receptor function in neurons. Finally, dexmedetomidine attenuated memory and problem-solving deficits after anesthesia. Conclusions: Dexmedetomidine prevented excessive &agr;5 &ggr;-aminobutyric acid type A receptor function after anesthesia. This novel &agr;2 adrenergic receptor- and brain-derived neurotrophic factor-dependent pathway may be targeted to prevent delirium.

Preventing delirium: beyond dexmedetomidine

www.thelancet.com Vol 389 March 11, 2017 1009 Authors’ reply We thank Sinziana Avramescu and colleagues for their comments regarding the underlying mechanism of dexmedetomidine to reduce delirium in elderly patients in the intensive care unit after surgery. We agree that the reduction of delirium incidence seen after treatment with low-dose dexmedetomidine infusion might occur because of the drug’s neuroprotective highly monitored intensive care unit settings because of its cardiorespiratory side-effects. However, millions of patients have delirium on medical wards, in palliative care centres, and nursing homes. If dexmedetomidine has direct neuroprotective properties, analogues with fewer side-effects could be developed. Such a discovery would represent a substantial pharmacological breakthrough and would reduce the substantial health-care costs associated with delirium (eg, US

Anesthesia research training: preparing for the future of our speciality.

164 billion per year in the USA). The search for an answer to this fundamental question would benefit from robust, novel animal models of delirium, and studies to advance understanding of the underlying molecular mechanisms of dexmedetomidine. For patients and health-care providers who manage the vexing problem of delirium, the answers to these questions and effective treatments cannot come soon enough.