Summary: A new study shows that prenatal disruption of the endocannabinoid system can have long-lasting effects on brain structure and behavior. When scientists lowered the activity of an endocannabinoid receptor in the developing mouse brain, neurons failed to migrate properly, and key genes involved in brain development were altered.
After birth, these mice displayed reduced social interaction and movement difficulties, mirroring the cellular disruptions observed. The findings suggest that prenatal interference with this system, including through cannabis exposure, may increase risk for neuropsychiatric conditions involving social deficits.
Key Facts
- Neuronal Disruption: Prenatal receptor reduction led to abnormal neuron migration in the cortex.
- Gene Changes: Genes tied to brain development and signaling were altered.
- Behavioral Impact: Offspring showed social and motor impairments linked to neural disruptions.
Source: SfN
Endocannabinoids are similar to the cannabinoids present in cannabis, but they are found naturally in the body.
Endocannabinoids—and cannabinoids—work through a signaling system that supports neurodevelopment, but whether manipulating this system prenatally has long-lasting effects remains unclear.
In a new Journal of Neuroscience paper, researchers led by Ismael Galve-Roperh, from the Complutense University of Madrid, used mice to explore this unknown.
The researchers decreased expression of an endocannabinoid receptor in the prefrontal cortex of prenatal mice and assessed the impact of this manipulation on gene expression, neural properties, and behavior after the mice were born.
Cortical neurons of the offspring did not migrate to their proper locations in the brain.
Additionally, these mice had altered expression of genes related to cortex development, neuron structure, and neural signaling.
On a behavioral level, the prenatal manipulation that lowered expression of this endocannabinoid receptor impaired social interaction and movement in offspring. These behavioral differences were reflective of the genetic and cellular changes that the researchers observed.
According to the researchers, this work suggests that hindering development by manipulating this system prenatally may lead to neuropsychiatric conditions, especially those involving social deficits.
Because cannabis acts through the same receptor the authors manipulated in this study, this work has implications on the understanding of prenatal cannabis exposure.
About this neurodevelopment and behavioral neuroscience research news
Author: SfN Media
Source: SfN
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Original Research: Closed access.
“Prenatal Downregulation of CB1 Cannabinoid Receptors in the Mouse Prefrontal Cortex Disrupts Cortical Lamination and Induces a Transcriptional Signature Associated with Social Interaction Deficits” by Ismael Galve-Roperh et al. Journal of Neuroscience
Abstract
Prenatal Downregulation of CB1 Cannabinoid Receptors in the Mouse Prefrontal Cortex Disrupts Cortical Lamination and Induces a Transcriptional Signature Associated with Social Interaction Deficits
Endocannabinoid signaling exerts a neurodevelopmental regulatory role via CB1 cannabinoid receptors (CB1Rs), which control pyramidal neuron differentiation, migration, and axonal guidance.
Here, we investigated the long-lasting consequences of transient prenatal CB1R downregulation within the mouse prefrontal cortex by assessing its impact on gene expression, neuronal electrophysiological properties, and animal behavioral traits.
Transient loss of CB1Rs as induced by in-utero small-interference (si) RNA electroporation at E14.5, when upper-layer neurons are generated, arrested cell migration leading to ectopic neurons that populated deep layers.
Whole cell-current clamp recordings showed that ectopic neurons are less excitable (increased afterhyperpolarization amplitude, decreased sag, lowe firing frequency) than deep layer-native pyramidal neurons.
Differentially expressed genes (DEGs), identified by microarray characterization of FACS-sorted electroporated neurons were significantly enriched in pathways related to cortical development, regulation of cell migration, neurotransmitter secretion, and cytoskeletal organization.
Gene set enrichment analysis also supported enrichment in pathways associated with neurodegenerative disorders and synaptic function.
The gene expression profile of siCB1R-derived neurons showed DEGs that had been previously associated with intellectual disability, schizophrenia, and autism.
Venn diagrams unveiled one common DEG for neuropsychiatric risk databases and CB1R expression manipulation, namely the transcription factor ZBTB20.
Prenatal knockdown of CB1Rs induced long-lasting behavioral alterations in the adult offspring of either sex, with an impairment of social interaction and motor behavior in siCB1R-derived adult mice.
Taken together, these findings highlight the role of CB1Rs in controlling the development of pyramidal neurons in the prefrontal cortex and support the contribution of altered endocannabinoid signaling to neuropsychiatric vulnerability.
