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. 2015 Oct;52(2):952-8.
doi: 10.1007/s12035-015-9247-6. Epub 2015 Jun 6.

Early Exposure to General Anesthesia with Isoflurane Downregulates Inhibitory Synaptic Neurotransmission in the Rat Thalamus

Pavle M Joksovic  1 , Nadia Lunardi, Vesna Jevtovic-Todorovic, Slobodan M Todorovic
Affiliations

Early Exposure to General Anesthesia with Isoflurane Downregulates Inhibitory Synaptic Neurotransmission in the Rat Thalamus

Pavle M Joksovic et al. Mol Neurobiol. 2015 Oct.

Abstract

Recent evidence supports the idea that common general anesthetics (GAs) such as isoflurane (Iso) and nitrous oxide (N2O; laughing gas) are neurotoxic and may harm the developing mammalian brain, including the thalamus; however, to date very little is known about how developmental exposure to GAs may affect synaptic transmission in the thalamus which, in turn, controls the function of thalamocortical circuitry. To address this issue we used in vitro patch-clamp recordings of evoked inhibitory postsynaptic currents (eIPSCs) from intact neurons of the nucleus reticularis thalami (nRT) in brain slices from rat pups (postnatal age P10-P18) exposed at age of P7 to clinically relevant GA combinations of Iso and N2O. We found that rats exposed to a combination of 0.75 % Iso and 75 % N2O display lasting reduction in the amplitude and faster decays of eIPSCs. Exposure to sub-anesthetic concentrations of 75 % N2O alone or 0.75 % Iso alone at P7 did not affect the amplitude of eIPSCs; however, Iso alone, but not N2O, significantly accelerated decay of eIPSCs. Anesthesia with 1.5 % Iso alone decreased amplitudes, caused faster decay and decreased the paired-pulse ratio of eIPSCs. We conclude that anesthesia at P7 with Iso alone or in combination with N2O causes plasticity of eIPSCs in nRT neurons by both presynaptic and postsynaptic mechanisms. We hypothesize that changes in inhibitory synaptic transmission in the thalamus induced by GAs may contribute to altered neuronal excitability and consequently abnormal thalamocortical oscillations later in life.

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Figures

Figure 1
Figure 1
Scheme depicts timeline of events in our experimental procedures.
Figure 2
Figure 2. Decreased synaptic strength of eIPSCs in rat pups exposed to the combination of 0.75% Iso and 75% N2O
A: Panel depicts family of inward eIPSCs evoked with escalating amplitudes of pulse stimuli (P1) in a representative nRT neuron from GA-treated rat. B: Average I-O curves from multiple experiments are plotted. Numbers in parenthesis indicate number of neurons in each condition.
Figure 3
Figure 3. Plasticity of eIPSCs in rat pups exposed to the combination of 0.75% Iso and 75% N2O
A: Paired-pulse stimulus protocol shows two stimuli (designated as P1 and P2) separated by 1 second and the trace of resulting eIPSC in a representative nRT neuron from a rat exposed to the anesthetic double combination. B: Bar graph shows that in GA-treated animals, the average PPR ratio is not significantly decreased as compared with that in sham-treated animals. C: Bar graph shows that in GA-treated animals, the average decay τ of eIPSCs is significantly decreased about 25% as compared with that in sham-treated animals.
Figure 4
Figure 4. Plasticity and decreased synaptic strength of eIPSCs in rat pups exposed to anesthesia with 0.75% Iso or 1.5% Iso alone
A: This panel depicts average traces from nRT neurons from the sham group (black trace, 24 neurons) and the GA-exposed groups with 0.75% Iso (gray trace, 13 neurons) and 1.5% Iso (red trace, 11 neurons). Note that only 1.5% Iso robustly decreased the amplitude of eIPSCs; but faster decay τs of eIPSCs are evident in both GA groups. B: The average decay time constants of eIPSCs are decreased significantly in the nRT neurons from both GA groups (gray bar- 0.75% Iso; red bar- 1.5% Iso) as compared with the nRT neurons from sham controls (black bar). C: Bar graph shows that in nRT neurons from 1.5% Iso-treated animals (red bar) the average PPR ratio is decreased significantly as compared with the nRT neurons from sham-treated animals (black bar). D: The averaged data from I-O curves show decreased synaptic strength of eIPSCs across the stimuli in the GA group treated with 1.5% Iso (red bars) versus the sham group (black bars).
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