Abstract
Brain development is a complex process regulated by genetic programs and activity-dependent neuronal connectivity. Anesthetics profoundly alter neuronal excitability, and anesthesia during early brain development has been consistently associated with neuroapoptosis, altered synaptogenesis, and persistent behavioral abnormalities in experimental animals. However, the depth, and even more the duration and developmental time point(s) of exposure to anesthesia determine the neuropathological and long-term behavioral consequences of anesthetics. Here, we have investigated adulthood phenotypic changes induced by repeated but brief (30 min) isoflurane anesthesia delivered during two distinct developmental periods in male mice. A set of animals were subjected to anesthesia treatments at postnatal days 7, 8 and 9 (P7-9) when the animals are susceptible to anesthesia-induced neuroapoptosis and reduced synaptogenesis. To control the potential influence of (handling) stress, a separate group of animals underwent repeated maternal separations of similar durations. Another set of animals were exposed to the same treatments at postnatal days 15, 16 and 17 (P15-17), a developmental time period when anesthetics have been shown to increase synaptogenesis. Starting from postnatal week 9 the mouse phenotype was evaluated using a battery of behavioral tests that assess general locomotor activity (home cage activity, open field), learning and memory (water maze) and depression- (saccharin preference, forced swim test), anxiety- (light-dark box, stress-induced hyperthermia) and schizophrenia- (nesting, prepulse inhibition) related endophenotypes. Apart from mild impairment in spatial navigation memory, exposure to anesthesia treatments during P7-9 did not bring obvious behavioral alterations in adult animals. Importantly, maternal separation during the same developmental period produced a very similar phenotype during the water maze. Mice exposed to anesthesia during P15-17 showed mild hyperactivity and risk-taking behavior in adulthood, but were otherwise normal. We conclude that significantly longer administration periods are needed in order for early-life repeated exposures to anesthetics to produce behavioral alterations in adult mice.
Highlights
Anesthetics primarily act through facilitating GABAA receptor function and/or dampening the glutamatergic NMDA (N-methyl-D-aspartate) receptor activity [1]
Male mouse pups were subjected to 30-minute isoflurane anesthesia or maternal separation on three consecutive days at either P7-9 or P15-17, or were left unhandled (Fig 1)
A recent study utilized a shorter duration of general anesthesia in rats during different stages of postnatal development [8]
Summary
Anesthetics produce concentration-dependent general anesthesia (unconsciousness, insensateness, analgesia and amnesia). General anesthetics are widely used in various medical practices requiring (surgical) anesthesia. Along with the continuous advances in modern preclinical invasive techniques (e.g. in vivo imaging), the use of anesthetics is steadily growing in biomedical research involving immature animals. Most general anesthetics, such as volatile halogenated hydrocarbons (e.g. isoflurane, sevoflurane), have relatively short half-lives which allows for rapid recovery following drug discontinuation. Anesthetics primarily act through facilitating GABAA receptor function and/or dampening the glutamatergic NMDA (N-methyl-D-aspartate) receptor activity [1]. GABAA receptors are chloride channels activated by GABA (gamma-aminobutyric acid), and are responsible for inhibitory synaptic transmission in the adult brain
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