Miswiring the brain: Δ9-tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin-2 degradation pathway.
Children exposed in utero to cannabis present permanent neurobehavioral and cognitive impairments. Psychoactive constituents from Cannabis spp., particularly Δ(9)-tetrahydrocannabinol (THC), bind to cannabinoid receptors in the fetal brain. However, it is unknown whether THC can trigger a cannabinoid receptor-driven molecular cascade to disrupt neuronal specification. Here, we show that repeated THC exposure disrupts endocannabinoid signaling, particularly the temporal dynamics of CB1 cannabinoid receptor, to rewire the fetal cortical circuitry. By interrogating the THC-sensitive neuronal proteome we identify Superior Cervical Ganglion 10 (SCG10)/stathmin-2, a microtubule-binding protein in axons, as a substrate of altered neuronal connectivity. We find SCG10 mRNA and protein reduced in the hippocampus of midgestational human cannabis-exposed fetuses, defining SCG10 as the first cannabis-driven molecular effector in the developing cerebrum. CB1 cannabinoid receptor activation recruits c-Jun N-terminal kinases to phosphorylate SCG10, promoting its rapid degradation in situ in motile axons and microtubule stabilization. Thus, THC enables ectopic formation of filopodia and alters axon morphology. These data highlight the maintenance of cytoskeletal dynamics as a molecular target for cannabis, whose imbalance can limit the computational power of neuronal circuitries in affected offspring.
Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Giuseppe
G
Tortoriello
Claudia V
CV
Morris
Alan
A
Alpar
Janos
J
Fuzik
Sally L
SL
Shirran
Daniela
D
Calvigioni
Erik
E
Keimpema
Catherine H
CH
Botting
Kirstin
K
Reinecke
Thomas
T
Herdegen
Michael
M
Courtney
Yasmin L
YL
Hurd
Tibor
T
Harkany
D000818:Animals; D001369:Axons / Q000187:drug effects; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000196:embryology; D013759:Dronabinol / Q000494:pharmacology*; D005260:Female; D005333:Fetus / Q000002:abnormalities / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000196:embryology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011247:Pregnancy; D040901:Proteomics; D011619:Psychotropic Drugs / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D050777:Stathmin; D013997:Time Factors
D002135:Calcium-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011619:Psychotropic Drugs; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D050777:Stathmin; C512849:Stmn2 protein, mouse; D013759:Dronabinol