Developmental cell death is enhanced in the cerebral cortex of mice lacking the brain vesicular monoamine transporter.
Neurotransmitters have emerged as important players in the control of programmed cell death in the cerebral cortex. We report that genetic depletion of serotonin, dopamine, and norepinephrine in mice lacking the vesicular monoamine transporter (VMAT2 KO mice) causes an increase in cell death in the superficial layers of the cingulate and retrosplenial cortices during early postnatal life (postnatal days 0-4). Electron microscopy and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling indicated that this represents a form of apoptosis. Caspase-3 and -9 are over activated in the VMAT2 KO cortex and Bcl-X(L) is downregulated, whereas the apoptosis-inducing factor caspase-8 and FasL/FasR pathway are not involved. Partial inhibition of serotonin or/and catecholamine synthesis by pharmacological treatments or genetic reduction of serotonin neuron number in mice lacking the transcription factor Pet-1 (pheochromocytoma 12 E26 transformation-specific) did not modify the cell death ratios in the cerebral cortex. However, when monoamine oxidase type A was invalidated in the VMAT2 KO background (VMAT2-MAOA DKO mice), increases in 5-HT levels coincided with a reduction of cell death and a normalization of Bcl-X(L) expression. trkB signaling is not implicated in the anti-apoptotic effects of MAOA inhibition because BDNF mRNA levels were unchanged in VMAT2-MAOA DKO mice and because the massive cell death in the cerebral cortex of trkB KO mice is also reverted by genetic invalidation of the MAOA gene. Finally the broad 5-HT2 receptor agonist (-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride prevented the increase in cell death of VMAT2 KO mice. Altogether, these results suggest that high levels of serotonin, acting through 5-HT2 receptors, have neuroprotective action on cortical neurons by controlling Bcl-X(L) mRNA levels and that this action is independent of trkB signaling.
Stankovski
Léa
L
Institut National de la Santé et de la Recherche Médicale, Unité 616, Institut Fédératif de Recherche Neurosciences, Hôpital de la Pitié-Salpêtrière, 75651 Paris, France.
Alvarez
Chantal
C
Ouimet
Tanja
T
Vitalis
Tania
T
El-Hachimi
Khalid H
KH
Price
David
D
Deneris
Evan
E
Gaspar
Patricia
P
Cases
Olivier
O
D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000502:physiology; D053453:Caspase 9 / Q000502:physiology; D002540:Cerebral Cortex / Q000254:growth & development / Q000473:pathology*; D004298:Dopamine / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006179:Gyrus Cinguli / Q000254:growth & development / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008995:Monoamine Oxidase / Q000172:deficiency / Q000235:genetics; D009414:Nerve Growth Factors / Q000096:biosynthesis / Q000235:genetics; D009474:Neurons / Q000473:pathology; D009638:Norepinephrine / Q000502:physiology; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology; D044405:Receptor, Serotonin, 5-HT2C / Q000502:physiology; D012701:Serotonin / Q000502:physiology*; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D015398:Signal Transduction; D050493:Vesicular Monoamine Transport Proteins / Q000172:deficiency* / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000502:physiology; D051020:bcl-X Protein / Q000502:physiology
D000662:Amphetamines; C494827:Bax protein, mouse; C494812:Bcl2l1 protein, mouse; D009414:Nerve Growth Factors; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists; C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D012701:Serotonin; D008995:Monoamine Oxidase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D053453:Caspase 9; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; D004298:Dopamine; D009638:Norepinephrine