Inhibition of long-term potentiation by valproic acid through modulation of cyclic AMP.
OBJECTIVE
Valproic acid (VPA) is widely used clinically in epilepsy, bipolar disorder, and migraine. In experimental models, it has also been shown to have neuroprotective and antiepileptogenic effects. Its mechanisms of action in these diverse conditions are, however, unclear, but there is some evidence indicating an effect of VPA upon protein kinase A (PKA) activity. We, therefore, asked whether VPA modulates cyclic adenosine monophosphate (cAMP)/PKA-dependent synaptic plasticity and whether this mode of action could explain its anticonvulsant effect.


METHODS
We first tested the effects of VPA on PKA-dependent synaptic plasticity at mossy fiber to CA3 synapses in rat hippocampus slices following very high-frequency stimulation or application of the adenylyl cyclase activator forskolin. Using biochemical assays, we then tested whether VPA had a direct effect on PKA activity or an indirect effect through modulating cAMP production. Lastly, VPA and inhibitors of adenylyl cyclase (SQ22536) and PKA (H89) were tested in in vitro models of epileptiform activity induced in hippocampal-entorhinal cortex slices using either pentylenetetrazol (2 mM) or low magnesium.


RESULTS
VPA (1 mm) inhibited PKA-dependent long-term potentiation of mossy fiber to CA3 pyramidal cell transmission. However, VPA did not directly modulate PKA activity but rather inhibited the accumulation of cAMP. In acute in vitro seizure models, the anticonvulsant activity of VPA is not mediated through modulation of adenylyl cyclase or PKA.


CONCLUSIONS
These results indicate that VPA through an action on cAMP accumulation can inhibit synaptic plasticity, but this cannot fully explain its anticonvulsant effect.
Chang
Pishan
P
UCL Institute of Neurology, University College London, London, UK.
Chandler
Kate E
KE
Williams
Robin S B
RS
Walker
Matthew C
MC
D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004827:Epilepsy / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007546:Isoquinolines / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology*
D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D013449:Sulfonamides; D014635:Valproic Acid; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide