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Neonatal Isoflurane Anesthesia or Disruption of Postsynaptic Density-95 Protein Interactions Change Dendritic Spine
Insights
Postnatal anesthesia exposure impairs brain development by affecting postsynaptic density-95 protein interactions, leading to long-term cognitive deficits in mice. Nitric oxide donors may prevent these anesthesia-induced effects.
Area of Science:
- Neuroscience
- Developmental Neuroscience
- Anesthesiology
Background:
- Postnatal exposure to anesthesia is linked to adverse effects on brain development.
- The postsynaptic density-95 (PSD-95) protein's PDZ2 domain is a target for inhaled anesthetics.
- Disrupting PSD-95 PDZ2 interactions early may cause lasting cognitive impairments.
Purpose of the Study:
- To investigate if early postnatal disruption of PSD-95 PDZ2 domain interactions leads to persistent deficits in dendritic spines and cognitive function.
- To explore the role of the nitric oxide synthase pathway in mediating anesthesia-induced neurodevelopmental changes.
Main Methods:
- One-week-old mice were exposed to isoflurane or a PDZ2 peptide targeting PSD-95.
- Control groups received saline or a non-targeting peptide.
- Cognitive functions, including object recognition and fear learning/memory, were assessed.
- Hippocampal spine density and long-term potentiation were evaluated.
- Mice received nitric oxide donors to assess preventative effects.
Main Results:
- Isoflurane and PDZ2 peptide exposure reduced mushroom spine density long-term.
- Both exposures resulted in deficits in object recognition and fear learning/memory.
- Long-term potentiation was impaired but recovered by 7 weeks.
- Nitric oxide donor administration prevented the isoflurane-induced decrease in mushroom spines.
Conclusions:
- Early disruption of PSD-95 PDZ2 interactions replicates anesthesia-induced effects on spine density and cognition.
- The nitric oxide synthase pathway is implicated in the cellular changes underlying cognitive impairment after anesthesia.
- Targeting PSD-95 interactions offers potential therapeutic avenues for mitigating anesthesia-related neurodevelopmental effects.
Background:
Experimental evidence shows postnatal exposure to anesthesia negatively affects brain development. The PDZ2 domain, mediating protein-protein interactions of the postsynaptic density-95 protein, serves as a molecular target for several inhaled anesthetics. The authors hypothesized that early postnatal disruption of postsynaptic density-95 PDZ2 domain interactions has persistent effects on dendritic spines and cognitive function.
Methods:
One-week-old mice were exposed to 1.5% isoflurane for 4 h or injected with 8 mg/kg active postsynaptic density-95 wild-type PDZ2 peptide along with their respective controls. A subset of these mice also received 4 mg/kg of the nitric oxide donor molsidomine. Hippocampal spine density, long-term potentiation, novel object recognition memory, and fear learning and memory were evaluated in mice.
Results:
Exposure of 7-day-old mice to isoflurane or postsynaptic density-95 wild-type PDZ2 peptide relative to controls causes: (1) a long-term decrease in mushroom spines at 7 weeks (mean ± SD [spines per micrometer]): control (0.8 ± 0.2) versus isoflurane (0.4 ± 0.2), P < 0.0001, and PDZ2MUT (0.7 ± 0.2) versus PDZ2WT (0.4 ± 0.2), P < 0.001; (2) deficits in object recognition at 6 weeks (mean ± SD [recognition index]): naïve (70 ± 8) versus isoflurane (55 ± 14), P = 0.010, and control (65 ± 13) versus isoflurane (55 ± 14), P = 0.045, and PDZ2MUT (64 ±11) versus PDZ2WT (53 ± 18), P = 0.045; and (3) deficits in fear learning at 7 weeks and memory at 8 weeks (mean ± SD [% freezing duration]): Learning, control (69 ± 12) versus isoflurane (52 ± 13), P < 0.0001, and PDZ2MUT (65 ± 14) versus PDZ2WT (55 ± 14) P = 0.011, and Memory, control (80 ± 17) versus isoflurane (56 ± 23), P < 0.0001 and PDZ2MUT (73 ± 18) versus PDZ2WT (44 ± 19) P < 0.0001. Impairment in long-term potentiation has fully recovered here at 7 weeks (mean ± SD [% baseline]): control (140 ± 3) versus isoflurane (137 ± 8), P = 0.560, and PDZ2MUT (136 ± 17) versus PDZ2WT (128 ± 11), P = 0.512. The isoflurane induced decrease in mushroom spines was preventable by introduction of a nitric oxide donor.
Conclusions:
Early disruption of PDZ2 domain-mediated protein-protein interactions mimics isoflurane in decreasing mushroom spine density and causing learning and memory deficits in mice. Prevention of the decrease in mushroom spine density with a nitric oxide donor supports a role for neuronal nitric oxide synthase pathway in mediating this cellular change associated with cognitive impairment.
