Inhibition of long‐term potentiation by valproic acid through modulation of cyclic AMP

Abstract

SUMMARYPurpose: 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 PKAdependent synaptic plasticity at mossy fiber to CA3 synapses in rat hippocampus slices following very highfrequency 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.

An in vitro model for synaptic loss in neurodegenerative diseases suggests a neuroprotective role for valproic acid via inhibition of cPLA2 dependent signalling

“…Therefore, the inhibition of cPLA2 by VPA and PIA may be beneficial under these conditions. However, long term VPA treatment is associated with impairment of hippocampal synaptic plasticity (Sgobio et al, 2010) and in vitro 1 mM VPA reduced long term potentiation in hippocampal slices (Chang et al, 2010) indicating that VPA and PIA may also reduce activation of cPLA2 in normal synapses.…”

The Phosphodiesterase 10A Inhibitor PF-2545920 Enhances Hippocampal Excitability and Seizure Activity Involving the Upregulation of GluA1 and NR2A in Post-synaptic Densities

“…(ii) Their study, which shows that repeated treatment with TAK-063 prevents striatal neurodegeneration, is focused on the mechanism by which TAK-063 blocks the reduction of BDNF levels. Our study showed that PF-2545920 enhances the excitability of pyramidal neurons and seizure activity possibly via activation of the cAMP–PKA pathway (Boulton et al, 1993; Chang et al, 2010; Lee, 2015). (iii) TAK-063, which has a faster off-rate, induces similar levels of activation in medium spiny neurons (MSNs) in the indirect pathway, while MSNs in the direct pathway are only partially activated (Suzuki et al, 2016).…”

“…Cyclic nucleotides, including cAMP and cGMP, act as second messenger signaling molecules and participate in numerous cellular functions in the CNS, including neurotransmitter specification, axon guidance, and refinement of neuronal connectivity (Averaimo and Nicol, 2014; Mu et al, 2014). In addition, a previous study showed that activation of the cAMP–PKA pathway increases excitability and enhances epileptiform activity in vitro (Boulton et al, 1993; Chang et al, 2010; Lee, 2015). …”

“…Papaverine, an intrinsic inhibitor of PDE10A, has been reported to cause seizures (Carhuapoma et al, 2001; Kahramaner et al, 2014), and the cAMP–PKA pathway plays a role in neuronal excitability of neurons (Boulton et al, 1993; Chang et al, 2010; Lee, 2015). Based on these data, we hypothesized that the PDE10A inhibitor PF-2545920 plays an important role in SE.…”

Potential Molecular and Cellular Mechanism of Psychotropic Drugs

“…It has been shown lithium increased activation of PKA leading to enhance the phosphorylation of GSK-3β80) and CREB in neuron-enriched cerebral cortical cultures from rats81) and in the intact rat brain 82). Conversely, VPA has been suggested to reduce forskolin-induced increase in cAMP levels in C6 rat glioma cells83) in the cultured cortical neurons84) and in the prefrontal cortex of rats 85). It remains unclear whether these mood stabilizers affect cAMP directly or indirectly by inhibiting the formation of cAMP.…”