Inhibition of RhoA reduces propofol-mediated growth cone collapse, axonal transport impairment, loss of synaptic connectivity, and behavioural deficits

Pearn, Matthew L.; Schilling, Jan M.; Jian, Minyu; Egawa, Junji; Wu, Chengbiao; Mandyam, Chitra D.; Fannon-Pavlich, M.J.; Nguyen, Uyen; Bertoglio, Jacques; Kodama, Mitsuyoshi; Mahata, S.K.; DerMardirossian, Céline; Lemkuil, Brian P.; Han, Ruquan; Mobley, William C.; Patel, Hemal H.; Patel, Piyush M.; Head, Brian P.

doi:10.1016/j.bja.2017.12.033

Cited by 34 publications

(40 citation statements)

References 116 publications

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“…these young neurones during this specific critical period of development that is interrupted and later manifests as behavioural impairment. This hypothesis is further supported by findings recently showing that maintaining synapses, 17 rather than preventing cell death, 16 protects from cognitive impairment. Our results, showing a difference in cognitive outcome in females at P4 vs P7 and a difference in the expression of chloride transporters, lend additional evidence to this argument.…”

Section: Discussionsupporting

confidence: 64%

Female rats are more vulnerable to lasting cognitive impairment after isoflurane exposure on postnatal day 4 than 7

Russell

Chinn

Maharjan

et al. 2019

British Journal of Anaesthesia

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Background: The factors determining peak susceptibility of the developing brain to anaesthetics are unclear. It is unknown why postnatal day 7 (P7) male rats are more vulnerable to anaesthesia-induced memory deficits than littermate females. Given the precocious development of certain regions in the female brain during the neonatal critical period, we hypothesised that females are susceptible to anaesthetic brain injury at an earlier time point than previously tested. Methods: Female rats were exposed to isoflurane (Iso) 1 minimum alveolar concentration or sham anaesthesia at P4 or P7. Starting at P35, rats underwent a series of behavioural tasks to test their spatial and recognition memory. Cell death immediately after anaesthesia was quantified by Fluoro-Jade C staining in select brain regions, and developmental expression of the chloride transporters KCC2 and NKCC1 was analysed by immunoblotting in male and female rats at P4 and P7. Results: Female rats exposed to Iso at P4 displayed impaired spatial, object-place, -context, and social recognition memory, and increased cell death in the hippocampus and laterodorsal thalamus. Female rats exposed at P7 exhibited only decreased performance in object-context compared with control. The ratio of NKCC1/KCC2 expression in cerebral cortex was higher in P4 females than in P7 females, and similar to that in P7 males. Conclusions: Female rats exposed to Iso at P4 are sensitive to anaesthetic injury historically observed in P7 males. This is consistent with a comparably immature developmental state in P4 females and P7 males. The window of anaesthetic vulnerability correlates with sex-specific cortical expression of chloride transporters NKCC1 and KCC2. These findings suggest that both sex and developmental age play important roles in determining the outcome after early anaesthesia exposure.

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Section: Discussionsupporting

confidence: 64%

Female rats are more vulnerable to lasting cognitive impairment after isoflurane exposure on postnatal day 4 than 7

Russell

Chinn

Maharjan

et al. 2019

British Journal of Anaesthesia

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“…Under normal cellular conditions, retrograde transport occurs when neurotrophins bind to plasmalemmal NTRs (TrkA, TrkB) followed by endocytosis and attachment to microtubules to facilitate intracellular transport down the axon. Evidence shows that impaired retrograde axonal transport occurs in many neurodegenerative conditions, such as Alzheimer disease, Parkinson disease, ALS, and anesthetic neurotoxicity (39)(40)(41)(42)(43). Neurotrophin/Trk signaling, growth cone motility, and synaptic modulation is dependent on MLRs (9,31,32).…”

Section: Discussionmentioning

confidence: 99%

Neuron‐targeted caveolin‐1 improves neuromuscular function and extends survival in SOD1 ^G93A mice

et al. 2019

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Interventions that preserve motor neurons or restore functional motor neuroplasticity may extend longevity in amyotrophic lateral sclerosis (ALS). Delivery of neurotrophins may potentially revive degenerating motor neurons, yet this approach is dependent on the proper subcellular localization of neurotrophin receptor (NTR) to plasmalemmal signaling microdomains, termed membrane/lipid rafts (MLRs). We previously showed that over‐expression of synapsin‐driven caveolin‐1 (Cav‐1) (SynCav1) increases MLR localization of NTR [e.g., receptor tyrosine kinase B (TrkB)], promotes hippocampal synaptic and neuroplasticity, and significantly improves learning and memory in aged mice. The present study crossed a SynCav1 transgene‐positive (SynCav1+) mouse with the mutant human superoxide dismutase glycine to alanine point mutation at amino acid 93 (hSOD1G93A) mouse model of ALS. When compared with hSOD1G93A, hSOD1G93A/SynCav1+ mice exhibited greater body weight and longer survival as well as better motor function. Microscopic analyses of hSOD1G93A/SynCav1+ spinal cords revealed preserved spinal cord α‐motor neurons and preserved mitochondrial morphology. Moreover, hSOD1G93A/SynCav1+ spinal cords contained more MLRs (cholera toxin subunit B positive) and MLR‐associated TrkB and Cav‐1 protein expression. These findings demonstrate that SynCav1 delays disease progression in a mouse model of ALS, potentially by preserving or restoring NTR expression and localization to MLRs.—Sawada, A., Wang, S., Jian, M., Leem, J., Wackerbarth, J., Egawa, J., Schilling, J. M., Platoshyn, O., Zemljic‐Harpf, A., Roth, D. M., Patel, H. H., Patel, P. M., Marsala, M., Head, B. P. Neuron‐targeted caveolin‐1 improves neuromuscular function and extends survival in SOD1G93A mice. FASEB J. 33, 7545–7554 (2019). http://www.fasebj.org

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“…Over polymerized actin are found to be associated with neural degeneration and cognitive dysfunction [16]. Previous studies have reported the reorganization of actin induced by propofol [6]. In one of our early research, we found increased F-actin level in old rat hippocampus after propofol anesthesia, which was closely related to the depression of LTP, indicating the important roles of overpolymerization of actin in synaptic dysfunction after propofol anesthesia [8].…”

Section: Discussionmentioning

confidence: 62%

“…For example, propofol has been reported to inhibit LTP [5]. It was also found to be able to modulate actin dynamics [6]. How about the status of actin dynamic after anesthesia?…”

Section: Introductionmentioning

confidence: 99%

Actin Reorganization in Hippocampal Neurons May Play Roles in Early Impairment of Learning and Memory in Rats After Propofol Anesthesia

Zhang¹,

Li²,

Wu³

2020

Preprint

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Background Perioperative neurocognitive disorder (PND) is a kind of neuronal complication especially observed in elderly patients. The present study was conducted to observe the changes of actin in hippocampus after propofol anesthesia, and to evaluate their roles in consequent learning impairment in both young (3-month-old) and aged (20-month-old) male rats.Methods Double-shuttle box was used to learning evaluation since1, 3, 7 or 14d after anesthesia. Hippocampi were removed after evaluations. F-actin content and the spines were observed through immunofluorescence and laser scanning confocal microscope (LSCM).Results In young rats, latency of escape response (LER) was prolonged within 3 days after anesthesia. However, LER was significantly prolonged until 7days after anesthesia in elderly rats. Moreover, the learning curves were also shift in old rats. Dendritic spines became smaller in anesthesia groups of aged rats within 3 days, where the F-actin contents were significantly increased until 14d post anesthesia.Conclusion Our results indicate that learning ability could be inhibited until after propofol anesthesia especially in old rats. The over-polymerization of actin and the consequent reorganization of dendrite spines in hippocampus may be responsible, which provides fresh evidence in aspect of synaptic plasticity for PND mechanism.

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Inhibition of RhoA reduces propofol-mediated growth cone collapse, axonal transport impairment, loss of synaptic connectivity, and behavioural deficits

Abstract: Inhibition of RhoA prevents propofol-mediated hippocampal neurotoxicity and associated cognitive deficits.

Cited by 34 publications

References 116 publications

Female rats are more vulnerable to lasting cognitive impairment after isoflurane exposure on postnatal day 4 than 7

Female rats are more vulnerable to lasting cognitive impairment after isoflurane exposure on postnatal day 4 than 7

Neuron‐targeted caveolin‐1 improves neuromuscular function and extends survival in SOD1 ^G93A mice

Actin Reorganization in Hippocampal Neurons May Play Roles in Early Impairment of Learning and Memory in Rats After Propofol Anesthesia

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Inhibition of RhoA reduces propofol-mediated growth cone collapse, axonal transport impairment, loss of synaptic connectivity, and behavioural deficits

Abstract: Inhibition of RhoA prevents propofol-mediated hippocampal neurotoxicity and associated cognitive deficits.

Cited by 34 publications

References 116 publications

Female rats are more vulnerable to lasting cognitive impairment after isoflurane exposure on postnatal day 4 than 7

Female rats are more vulnerable to lasting cognitive impairment after isoflurane exposure on postnatal day 4 than 7

Neuron‐targeted caveolin‐1 improves neuromuscular function and extends survival in SOD1 G93A mice

Actin Reorganization in Hippocampal Neurons May Play Roles in Early Impairment of Learning and Memory in Rats After Propofol Anesthesia

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Neuron‐targeted caveolin‐1 improves neuromuscular function and extends survival in SOD1 ^G93A mice