Abstract
Prior to sensory experience spontaneous activity appears to play a fundamental role in the correct formation of prominent functional features of different cortical regions. The use of anaesthesia during pregnancy such as ketamine is largely considered to negatively affect neuronal development by interfering with synaptic transmission. Interestingly, the characteristics of spontaneous activity as well as the acute functional effects of maternal anaesthesia remain largely untested in the embryonic cortex in vivo. In the present work, we performed in vivo imaging of spontaneous calcium activity and cell motility in the marginal zone of the cortex of E14-15 embryos connected to the mother. We made use of a preparation where the blood circulation from the mother through the umbilical cord is preserved and fluctuations in intracellular calcium in the embryonic frontal cortex are acquired using two-photon imaging. We found that spontaneous transients were either sporadic or correlated in clusters of neuronal ensembles at this age. These events were not sensitive to maternal isoflurane anaesthesia but were strongly inhibited by acute in situ or maternal application of low concentration of the anaesthetic ketamine (a non-competitive antagonist of NMDA receptors). Moreover, simultaneous imaging of cell motility revealed a correlated strong sensitivity to ketamine. These results show that anaesthetic compounds can differ significantly in their impact on spontaneous early cortical activity as well as motility of cells in the marginal zone. The effects found in this study may be relevant in the etiology of heightened vulnerability to cerebral dysfunction associated with the use of ketamine during pregnancy.
Highlights
The teratogenicity of exposure to anaesthetics during embryonic development in humans is under debate a consensus is that an increased vulnerability to cerebral dysfunction is associated with exposure to multiple anaesthetics[1]
We recently developed an in vivo two-photon method to image calcium activity in the mouse embryonic cortex[24,25]
At E15 embryos were subsequently in vivo loaded with Fluo-4AM. mCherry expression was found in radially migrating neurons as well as neurons at the marginal zone resembling the morphology of Cajal-Retzius cells
Summary
The teratogenicity of exposure to anaesthetics during embryonic development in humans is under debate a consensus is that an increased vulnerability to cerebral dysfunction is associated with exposure to multiple anaesthetics[1]. A subpopulation of loaded cells that were electroporated at E12 with a vector carrying mCherry displayed more mature morphology Using this approach, we show for the first time spontaneous cortical calcium activity in vivo, in a paradigm where the mother provides both the brain oxygenation and nutrition. We found that acute maternal ketamine anaesthesia strongly blocks spontaneous calcium activity and significantly reduced diverse forms of cellular motility in vivo These results show that anaesthetic compounds can differ significantly in their impact on spontaneous early cortical activity as well as motility of cells in the marginal zone. The effects found in this study may be relevant in the etiology of heightened vulnerability to cerebral dysfunction associated with the use of ketamine during pregnancy
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