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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM102525-01A1
Application #
8629876
Study Section
Special Emphasis Panel (ZRG1-SBIB-X (02))
Program Officer
Cole, Alison E
Project Start
2014-01-01
Project End
2017-11-30
Budget Start
2014-01-01
Budget End
2014-11-30
Support Year
1
Fiscal Year
2014
Total Cost
$310,932
Indirect Cost
$113,432
Name
University of Virginia
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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) 231:3503-15