The ability of the anesthetics to induce safe and reversible loss of consciousness is of paramount im- portance, yet new animal data suggest that general anesthetics that activate GABAA receptors and/or inhibit NMDA channels are neurotoxic for the developing mammalian brain and have implicated them in causing cognitive deficits later in life. Thus, further research into cellular mechanisms of currently availa- ble anesthetics and development of novel anesthetics, particularly for pediatric anesthesia, is warranted. Over the past decade, several studies have shown widespread neurodegeneration in various brain re- gions, including thalamic nuclei, in young rodents exposed to general anesthetics. However, the possible role of general anesthetics in causing lasting alterations of thalamocortical functioning is not well studied. Our data indicate that immature rats exposed to commonly used general anesthetics at age P7 exhibit lasting reduction in inhibitory synaptic transmission and concomitant plasticity of intrinsic ion channels in the nucleus reticularis thalami (nRT). We hypothesize that exposure to general anesthetics during early development causes reduction of inhibitory GABAergic transmission and up-regulation of T-channels in nRT, leading to chronic hyperexcitability of thalamocortical networks. To test this hypothesis, we will use in vitro patch-clamp recordings from native nRT and thalamocortical (TC) relay neurons and in vivo elec- troencephalographic (EEG) recordings to pursue the following specific aims:
Aim 1 : To determine whether rats exposed at P7 to the common volatile anesthetic isoflurane or the commonly used intravenous anesthetics propofol and ketamine will exhibit reduction in inhibitory GABAergic transmission of nRT neurons.
Aim 2 : To determine whether rats exposed at P7 to isoflurane exhibit up-regulation of T-channels in nRT neurons and whether such up-regulation, in turn, leads to an enhanced burst firing pattern in these cells.
Aim 3 : To determine whether lasting alterations in synaptic transmission and intrinsic ion channels in the thalamus caused by general anesthetics may lead to hyperexcitability of thalamocortical networks as assessed using EEG recordings in freely moving ani- mals.
Aim 4 : To determine whether thalamic T-current inhibition contributes to the hypnotic effects of the neuroactive steroid 3?OH, which is a T-channel blocker devoid of any effects on postsynaptic GABAA or NMDA receptors. We also will test the hypothesis that exposure of rat pups to 3?OH will have minimal impact on synaptic homeostasis and, thus, will not trigger neuronal hyperexcitability in the thalamus. The proposed work is innovative in that new mechanisms of anesthetic-induced synaptic and intrinsic neu- ronal plasticity will be characterized. It is medically significant because it documents important develop- mental alterations induced by short exposures to widely used clinical drugs and is expected to help iden- tify new targets for the development of safer anesthetics and practices in clinical anesthesia.

Public Health Relevance

This proposed research is relevant to public health since it will study acute and lasting effects of general anesthetics on ion channels in the developing thalamocortical circuitry. Every year tens of millions of patients including very young children ar exposed to general anesthetics and recent animal data suggest that various classes of common general anesthetics may harm the developing mammalian brain. The project is relevant to NIH's and NIGMS'mission because the findings are important for understanding cellular mechanisms of anesthesia and anesthetic-induced neuroplasticity, as well as potential development of novel, safer anesthetics.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-SBIB-X (02))
Program Officer
Cole, Alison E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Virginia
Schools of Medicine
United States
Zip Code
Tracy, Matthew E; Tesic, Vesna; Stamenic, Tamara Timic et al. (2018) CaV3.1 isoform of T-type calcium channels supports excitability of rat and mouse ventral tegmental area neurons. Neuropharmacology 135:343-354
Stamenic, Tamara Timic; Todorovic, Slobodan M (2018) Cytosolic ATP Relieves Voltage-Dependent Inactivation of T-Type Calcium Channels and Facilitates Excitability of Neurons in the Rat Central Medial Thalamus. eNeuro 5:
Joksimovic, Srdjan M; Osuru, Hari Prasad; Oklopcic, Azra et al. (2018) Histone Deacetylase Inhibitor Entinostat (MS-275) Restores Anesthesia-induced Alteration of Inhibitory Synaptic Transmission in the Developing Rat Hippocampus. Mol Neurobiol 55:222-228
Dalla Massara, Lorenza; Osuru, Hari Prasad; Oklopcic, Azra et al. (2016) General Anesthesia Causes Epigenetic Histone Modulation of c-Fos and Brain-derived Neurotrophic Factor, Target Genes Important for Neuronal Development in the Immature Rat Hippocampus. Anesthesiology 124:1311-1327
Wang, Guangfu; Bochorishvili, Genrieta; Chen, Yucai et al. (2015) CaV3.2 calcium channels control NMDA receptor-mediated transmission: a new mechanism for absence epilepsy. Genes Dev 29:1535-51
Joksovic, Pavle M; Lunardi, Nadia; Jevtovic-Todorovic, Vesna et al. (2015) Early Exposure to General Anesthesia with Isoflurane Downregulates Inhibitory Synaptic Neurotransmission in the Rat Thalamus. Mol Neurobiol 52:952-8
DiGruccio, Michael R; Joksimovic, Srdjan; Joksovic, Pavle M et al. (2015) Hyperexcitability of rat thalamocortical networks after exposure to general anesthesia during brain development. J Neurosci 35:1481-92
Ayoola, Christine; Hwang, Sung Mi; Hong, Sung Jun et al. (2014) Inhibition of CaV3.2 T-type calcium channels in peripheral sensory neurons contributes to analgesic properties of epipregnanolone. Psychopharmacology (Berl) 231:3503-3515