Isoflurane differentially affects neurogenesis and long-term neurocognitive function in 60-day-old and 7-day-old rats.
BACKGROUND
Anesthetic agents cause cell death in the developing rodent brain and long-term, mostly hippocampal-dependent, neurocognitive dysfunction. However, a causal link between these findings has not been shown. Postnatal hippocampal neurogenesis affects hippocampal function into adulthood; therefore, the authors tested the hypothesis that isoflurane affects long-term neurocognitive function via an effect on dentate gyrus neurogenesis.


METHODS
The S-phase marker 5-bromodeoxyuridine was administered at various times before, during, and after 4 h of isoflurane given to postnatal day (P)60 and P7 rats to assess dentate gyrus progenitor proliferation, early neuronal lineage selection, and long-term survival of new granule cell neurons. Fear conditioning and spatial reference memory was tested at various intervals from 2 weeks until 8 months after anesthesia.


RESULTS
In P60 rats, isoflurane increased early neuronal differentiation as assessed by BrdU/NeuroD costaining, decreased progenitor proliferation for 1 day, and subsequently increased progenitor proliferation 5-10 days after anesthesia. In P7 rats, isoflurane did not induce neuronal lineage selection but decreased progenitor proliferation until at least 5 days after anesthesia. Isoflurane improved spatial reference memory of P60 rats long-term, but it caused a delayed-onset, progressive, persistent hippocampal deficit in P7 rats in fear conditioning and spatial reference memory tasks.


CONCLUSIONS
The authors conclude that isoflurane differentially affects both neurogenesis and long-term neurocognitive function in P60 and P7 rats. Neurogenesis might mediate the long-term neurocognitive outcome after isoflurane at different ages.
Stratmann
Greg
G
Department of Anesthesia and Perioperative Care, University of California, San Francisco 94143, USA. stratman@anesthesia.ucsf.edu
Sall
Jeffrey W
JW
May
Laura D V
LD
Bell
Joseph S
JS
Magnusson
Kathy R
KR
Rau
Vinuta
V
Visrodia
Kavel H
KH
Alvi
Rehan S
RS
Ku
Ban
B
Lee
Michael T
MT
Dai
Ran
R
D000367:Age Factors; D018685:Anesthetics, Inhalation / Q000009:adverse effects*; D000818:Animals; D001973:Bromodeoxyuridine; D016923:Cell Death; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D003213:Conditioning, Psychological / Q000187:drug effects; D018891:Dentate Gyrus / Q000166:cytology / Q000187:drug effects*; D007530:Isoflurane / Q000009:adverse effects*; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D051381:Rats; D016896:Treatment Outcome
D018685:Anesthetics, Inhalation; D007530:Isoflurane; D001973:Bromodeoxyuridine