Valproic acid selectively suppresses the formation of inhibitory synapses in cultured cortical neurons.
Valproic acid (VPA) has been used to treat epileptic patients because of its ability to potentiate GABA signaling in the brain. Despite its clinical significance, VPA administration during pregnancy increases the risk of congenital abnormalities, such as neural tube defects and neurodevelopmental disorders including autism. Furthermore, recent studies revealed that early postnatal administration of VPA also leads to neurodevelopmental deficits in rodents. Here, using cultured cortical neurons derived from postnatal day 1 rats, we examined whether exposure to VPA would affect synapse formation. When neurons were exposed to 1mM VPA during early development, expression of the vesicular GABA transporter (VGAT) was selectively reduced, whereas other synaptic markers, including the vesicular glutamate transporters 1 and 2 (VGLUT1 and 2), were not affected. This VPA effect was mediated through inhibition of histone deacetylases (HDACs), since the effects were mostly recapitulated by an HDAC inhibitor, trichostatin A, but not by a VPA derivative, valpromide, which lacks HDAC inhibitor activity. Immunocytochemical analysis demonstrated that VPA exposure resulted in a retardation of axonal growth specific to GABAergic neurons and a decrease in VGAT-positive synapses. Since disturbance of the excitatory and inhibitory (E-I) balance has been implicated as a potential cause of multiple psychiatric disorders, our results may account for one of the cellular mechanisms underlying the pathogenesis of VPA-induced neurodevelopmental impairments.
Laboratory of Neural Membrane Biology, Graduate School of Brain Science, Doshisha University, 1-3 Miyakodani, Tatara, Kyotanabe-shi, Kyoto 610-0394, Japan. Electronic address: ekumamar@mail.doshisha.ac.jp.
Emi
E
Kumamaru
Laboratory of Neural Membrane Biology, Graduate School of Brain Science, Doshisha University, 1-3 Miyakodani, Tatara, Kyotanabe-shi, Kyoto 610-0394, Japan. Electronic address: yegashir@mail.doshisha.ac.jp.
Yoshihiro
Y
Egashira
Laboratory of Neural Membrane Biology, Graduate School of Brain Science, Doshisha University, 1-3 Miyakodani, Tatara, Kyotanabe-shi, Kyoto 610-0394, Japan. Electronic address: rie1989ta@yahoo.co.jp.
Rie
R
Takenaka
Laboratory of Neural Membrane Biology, Graduate School of Brain Science, Doshisha University, 1-3 Miyakodani, Tatara, Kyotanabe-shi, Kyoto 610-0394, Japan. Electronic address: stakamor@mail.doshisha.ac.jp.
Shigeo
S
Takamori
D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology*; D001369:Axons / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000254:growth & development; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D051381:Rats; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors; D014635:Valproic Acid / Q000494:pharmacology*; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000927:Anticonvulsants; D056572:Histone Deacetylase Inhibitors; C118623:Slc32a1 protein, rat; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; D005680:gamma-Aminobutyric Acid; D014635:Valproic Acid
Synapse formation; Valproic acid; Vesicular GABA transporter