Abstract
BackgroundThe soluble epoxide hydrolase (sEH) is an important enzyme chiefly involved in the metabolism of fatty acid signaling molecules termed epoxyeicosatrienoic acids (EETs). sEH inhibition (sEHI) has proven to be protective against experimental cerebral ischemia, and it is emerging as a therapeutic target for prevention and treatment of ischemic stroke. However, the role of sEH on synaptic function in the central nervous system is still largely unknown. This study aimed to test whether sEH C-terminal epoxide hydrolase inhibitor, 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA) affects basal synaptic transmission and synaptic plasticity in the prefrontal cortex area (PFC). Whole cell and extracellular recording examined the miniature excitatory postsynaptic currents (mEPSCs) and field excitatory postsynaptic potentials (fEPSPs); Western Blotting determined the protein levels of glutamate receptors and ERK phosphorylation in acute medial PFC slices.ResultsApplication of the sEH C-terminal epoxide hydrolase inhibitor, AUDA significantly increased the amplitude of mEPSCs and fEPSPs in prefrontal cortex neurons, while additionally enhancing long term potentiation (LTP). Western Blotting demonstrated that AUDA treatment increased the expression of the N-methyl-D-aspartate receptor (NMDA) subunits NR1, NR2A, NR2B; the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits GluR1, GluR2, and ERK phosphorylation.ConclusionsInhibition of sEH induced an enhancement of PFC neuronal synaptic neurotransmission. This enhancement of synaptic neurotransmission is associated with an enhanced postsynaptic glutamatergic receptor and postsynaptic glutamatergic receptor mediated synaptic LTP. LTP is enhanced via ERK phosphorylation resulting from the delivery of glutamate receptors into the PFC by post-synapse by treatment with AUDA. These findings provide a possible link between synaptic function and memory processes.
Highlights
The soluble epoxide hydrolase is an important enzyme involved in the metabolism of fatty acid signaling molecules termed epoxyeicosatrienoic acids (EETs). sEH inhibition has proven to be protective against experimental cerebral ischemia, and it is emerging as a therapeutic target for prevention and treatment of ischemic stroke
To examine whether the intrinsic excitability of prefrontal cortex area (PFC) neurons is changed by treatment of the sEH inhibitior AUDA, whole-cell patch clamp recordings were performed on PFC slices
Perfusion with 1, 5,10 μM of AUDA significantly enhanced the field excitatory postsynaptic potentials (fEPSPs) compared to vehicle control (F(3,16) = 36.3 P < 0.001)
Summary
The soluble epoxide hydrolase (sEH) is an important enzyme involved in the metabolism of fatty acid signaling molecules termed epoxyeicosatrienoic acids (EETs). sEH inhibition (sEHI) has proven to be protective against experimental cerebral ischemia, and it is emerging as a therapeutic target for prevention and treatment of ischemic stroke. This study aimed to test whether sEH C-terminal epoxide hydrolase inhibitor, 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA) affects basal synaptic transmission and synaptic plasticity in the prefrontal cortex area (PFC). Electrophysiology studies demonstrated that the C-terminal epoxide hydrolase (EH) inhibitor 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA) is elevated the endogenous EETs to increase neuronal activity in the hypothalamus and brain stem of SHR rats [12]. The 5,6-EET increases the spontaneous excitatory postsynaptic current (sEPSC) frequency in spinal cord slices to affect the pain sensitivity [17]. Together, these studies raise the possibility that the EETs could modulate the physiological actions through the enhancement of excitatory neurotransmitter and neuronal activity. How the sEH-EET affect the basal levels of glutamate within prefrontal cortex remain unclear
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