Early Exposure to Ketamine Impairs Axonal Pruning in Developing Mouse Hippocampus

Abstract

Mounting evidence suggests that prolonged exposure to general anesthesia (GA) during brain synaptogenesis damages the immature neurons and results in long-term neurocognitive impairments. Importantly, synaptogenesis relies on timely axon pruning to select axons that participate in active neural circuit formation. This process is in part dependent on proper homeostasis of neurotrophic factors, in particular brain-derived neurotrophic factor (BDNF). We set out to examine how GA may modulate axon maintenance and pruning and focused on the role of BDNF. We exposed post-natal day (PND)7 mice to ketamine using a well-established dosing regimen known to induce significant developmental neurotoxicity. We performed morphometric analyses of the infrapyramidal bundle (IPB) since IPB is known to undergo intense developmental modeling and as such is commonly used as a well-established model of in vivo pruning in rodents. When IPB remodeling was followed from PND10 until PND65, we noted a delay in axonal pruning in ketamine-treated animals when compared to controls; this impairment coincided with ketamine-induced downregulation in BDNF protein expression and maturation suggesting two conclusions: a surge in BDNF protein expression "signals" intense IPB pruning in control animals and ketamine-induced downregulation of BDNF synthesis and maturation could contribute to impaired IPB pruning. We conclude that the combined effects on BDNF homeostasis and impaired axon pruning may in part explain ketamine-induced impairment of neuronal circuitry formation.

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

“…111,112 Further investigation is needed to better understand why other anaesthetics, such as ketamine, affect the infrapyramidal bundle differently than propofol; for example, ketamine exposure of neonatal rodents results in decreased infrapyramidal pruning. 113 Propofol acts primarily through gaminobutyric acid agonism, while ketamine acts through Nmethyl-D-aspartate receptor antagonism. There is evidence for a complex interplay between dimethylnitrosamine receptor activity and Rho GTPase activation.…”

Repeated neonatal isoflurane exposures in the mouse induce apoptotic degenerative changes in the brain and relatively mild long-term behavioral deficits

“…Animal studies have shown that one type of acute damage to the developing brain induced by AASDs is increased apoptotic neurodegeneration, which likely involves N-methyl-D-aspartate (NMDA) glutamate receptor antagonism or potentiation of γ-aminobutyric acid A (GABA A ) receptors 12 . Recent animal studies have shown AASDs also impair neuronal function by disturbing timely axonal pruning and cues that promote accurate directional growth of axons during development 13,14 . Preclinical research has been valuable in defining the spatial and temporal patterns of the acute apoptotic damage, which is widespread and includes cell-type-specific patterns 1–3 .…”

GABAergic neurons are susceptible to BAX-dependent apoptosis following isoflurane exposure in the neonatal period

“…This study was prompted by the finding that in addition to neuron death, exposure to anesthetic agents in the neonatal period results in disrupted synapse architecture, mitochondrial morphology and axonal pruning [37][38][39]. We attempted to delineate the contribution of neuron death from other potentially injurious effects associated with exposure to volatile anesthetics in the neonatal period using Bax knockout mice.…”