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Ketamine affects the integration of developmentally generated granule neurons in the adult stage
he huang
first affiliated hospital with Nanjing medical university
Corresponding Author
ORCiD: https://orcid.org/0000-0003-1573-1204
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at BMC Neuroscience.
Background Ketamine has been reported to cause neonatal neurotoxicity in a variety of developing animal models. Various studies have been conducted to study the mechanism of neurotoxicity for general anesthetic use during the neonatal period. Previous experiments have suggested that developmentally generated granule neurons in the hippocampus dentate gyrus (DG) supported hippocampus-dependent memory. Therefore, this study aimed to investigate whether ketamine affects the functional integration of developmentally generated granule neurons in the DG. For this purpose，the postnatal day 7 (PND-7) Sprague-Dawley (SD) rats were divided into the control group and the ketamine group (rats who received 4 injections of 40 mg/kg ketamine at 1 h intervals). To label dividing cells, BrdU was administered for three consecutive days after the ketamine exposure; NeuN+/BrdU+ cells were observed by using immunofluorescence. To evaluate the developmentally generated granule neurons that support hippocampus-dependent memory, spatial reference memory was tested by using Morris Water Maze at 3 months old, after which the immunofluorescence was used to detect c-Fos expression in the NeuN+/BrdU+ cells. The expression of caspase-3 was measured by Western blot to detect the apoptosis in the hippocampal DG.ResultsThe present results showed that the neonatal ketamine exposure did not influence the survival rate of developmentally generated granule neurons at 2 and 3 months old, but ketamine interfered with the integration of these neurons into the hippocampal DG neural circuits and caused a deficit in hippocampal-dependent spatial reference memory tasks.ConclusionsIn summary, these findings may promote more studies to investigate the neurotoxicity of ketamine in the developing brain.
Keywords
Ketamine; Dentate gyrus; Functional integration; Neural circuits; Morris water maze; Learning; Rat
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Received 28 Jul, 2019
Reviewer #2 agreed
On 26 Jul, 2019
Reviewer #1 agreed
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Developmental Neuroscience
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This preprint is under consideration at BMC Neuroscience. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research article
Ketamine affects the integration of developmentally generated granule neurons in the adult stage
he huang
first affiliated hospital with Nanjing medical university
Corresponding Author
ORCiD: https://orcid.org/0000-0003-1573-1204
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
Version 4
Posted 18 Dec, 2019
Published
On 18 Dec, 2019
No community comments so far
Editorial decision: Accept
On 06 Dec, 2019
Editor assigned
On 05 Dec, 2019
Submission checks complete
On 04 Dec, 2019
Editor invited
On 04 Dec, 2019
No comments provided
Editorial decision: Minor revision
On 03 Dec, 2019
Reviewer #2 agreed
On 21 Nov, 2019
Reviewer #1 agreed
On 20 Nov, 2019
Reviewers invited
Invitations sent on 16 Nov, 2019
Editor assigned
On 31 Oct, 2019
Submission checks complete
On 30 Oct, 2019
Editor invited
On 30 Oct, 2019
No comments provided
Review #2 received
Received 25 Oct, 2019
Editorial decision: Minor revision
On 25 Oct, 2019
Review #1 received
Received 11 Oct, 2019
Reviewer #2 agreed
On 16 Sep, 2019
Editor assigned
On 11 Sep, 2019
Reviewers invited
Invitations sent on 11 Sep, 2019
Reviewer #1 agreed
On 11 Sep, 2019
Submission checks complete
On 10 Sep, 2019
Editor invited
On 10 Sep, 2019
No comments provided
Editorial decision: Major revision
On 12 Aug, 2019
Review #2 received
Received 09 Aug, 2019
Review #1 received
Received 28 Jul, 2019
Reviewer #2 agreed
On 26 Jul, 2019
Reviewer #1 agreed
On 15 Jul, 2019
Reviewers invited
Invitations sent on 23 Jun, 2019
Submission checks complete
On 17 Jun, 2019
Editor invited
On 17 Jun, 2019
Editor assigned
On 17 Jun, 2019
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Developmental Neuroscience
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at BMC Neuroscience.
Background Ketamine has been reported to cause neonatal neurotoxicity in a variety of developing animal models. Various studies have been conducted to study the mechanism of neurotoxicity for general anesthetic use during the neonatal period. Previous experiments have suggested that developmentally generated granule neurons in the hippocampus dentate gyrus (DG) supported hippocampus-dependent memory. Therefore, this study aimed to investigate whether ketamine affects the functional integration of developmentally generated granule neurons in the DG. For this purpose，the postnatal day 7 (PND-7) Sprague-Dawley (SD) rats were divided into the control group and the ketamine group (rats who received 4 injections of 40 mg/kg ketamine at 1 h intervals). To label dividing cells, BrdU was administered for three consecutive days after the ketamine exposure; NeuN+/BrdU+ cells were observed by using immunofluorescence. To evaluate the developmentally generated granule neurons that support hippocampus-dependent memory, spatial reference memory was tested by using Morris Water Maze at 3 months old, after which the immunofluorescence was used to detect c-Fos expression in the NeuN+/BrdU+ cells. The expression of caspase-3 was measured by Western blot to detect the apoptosis in the hippocampal DG.ResultsThe present results showed that the neonatal ketamine exposure did not influence the survival rate of developmentally generated granule neurons at 2 and 3 months old, but ketamine interfered with the integration of these neurons into the hippocampal DG neural circuits and caused a deficit in hippocampal-dependent spatial reference memory tasks.ConclusionsIn summary, these findings may promote more studies to investigate the neurotoxicity of ketamine in the developing brain.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5