Isoflurane reversibly destabilizes hippocampal dendritic spines by an actin-dependent mechanism.

Jimcy Platholi,Karl F Herold,Hugh C Hemmings,Shelley Halpain,Daqing Ma

doi:10.1371/journal.pone.0102978

Abstract

General anesthetics produce a reversible coma-like state through modulation of excitatory and inhibitory synaptic transmission. Recent evidence suggests that anesthetic exposure can also lead to sustained cognitive dysfunction. However, the subcellular effects of anesthetics on the structure of established synapses are not known. We investigated effects of the widely used volatile anesthetic isoflurane on the structural stability of hippocampal dendritic spines, a postsynaptic structure critical to excitatory synaptic transmission in learning and memory. Exposure to clinical concentrations of isoflurane induced rapid and non-uniform shrinkage and loss of dendritic spines in mature cultured rat hippocampal neurons. Spine shrinkage was associated with a reduction in spine F-actin concentration. Spine loss was prevented by either jasplakinolide or cytochalasin D, drugs that prevent F-actin disassembly. Isoflurane-induced spine shrinkage and loss were reversible upon isoflurane elimination. Thus, isoflurane destabilizes spine F-actin, resulting in changes to dendritic spine morphology and number. These findings support an actin-based mechanism for isoflurane-induced alterations of synaptic structure in the hippocampus. These reversible alterations in dendritic spine structure have important implications for acute anesthetic effects on excitatory synaptic transmission and synaptic stability in the hippocampus, a locus for anesthetic-induced amnesia, and have important implications for anesthetic effects on synaptic plasticity.

Highlights

The mechanisms underlying general anesthesia, a reversible pharmacologic coma-like state characterized by amnesia, loss of consciousness and immobility, remain poorly understood
Isoflurane reduces dendritic spine density and shrinks remaining spines We used rat hippocampal neurons cultured for 3 weeks prior to experimental treatments to examine the effects of isoflurane on mature dendritic spines at established synapses [37]
Spine density (Fig. 4B) and spine area (Fig. 4C) returned to control values within 40 min of isoflurane wash-out following a 20 min exposure. This recovery in spine number and shape was stable up to 12 h. These results suggest that isoflurane-induced effects on dendritic spine morphology and number are reversible, and recover upon isoflurane elimination

Summary

Introduction

The mechanisms underlying general anesthesia, a reversible pharmacologic coma-like state characterized by amnesia, loss of consciousness and immobility, remain poorly understood. No singular molecular or cellular target has been identified that can explain these diverse effects, volatile anesthetics are known to regulate synaptic transmission by modulating various ligand- and voltage-gated ion channels at synaptic and extrasynaptic sites [1,2]. While these effects have been assumed to be fully reversible upon drug elimination, recent evidence suggests that exposure of the early postnatal or aging brain to anesthetics can induce long-lasting impairment in cognitive function and synaptic plasticity [3,4]. Alterations in spine number and shape are associated with cognitive and developmental dysfunction in various neurological disorders [7]

Methods

Results

Conclusion