Differential Effects of the Histamine H₃Receptor Agonist Methimepip on Dentate Granule Cell Excitability, Paired-Pulse Plasticity and Long-Term Potentiation in Prenatal Alcohol-Exposed Rats

Abstract

We previously reported that prenatal alcohol-induced deficits in dentate gyrus (DG) long-term potentiation (LTP) are ameliorated by the histamine H3 receptor inverse agonist ABT-239. ABT-239 did not enhance LTP in control rats, suggesting a heightened H3 receptor-mediated inhibition of glutamate release in prenatal alcohol-exposed (PAE) offspring. As the modulation of glutamate release is one important facet of LTP, we examined the effect of methimepip, a histamine H3 receptor agonist, on DG granule cell excitability, glutamate release and LTP in control and PAE rats. Long-Evans rat dams voluntarily consumed either a 0% or 5% ethanol solution four hours daily throughout gestation. Male adult offspring were anesthetized with urethane and electrodes implanted into the entorhinal cortex and DG. PAE reduced coupling of excitatory post-synaptic field potentials to population spikes, an effect mimicked in control rats treated with 1 mg/kg methimepip. Methimepip decreased release probability in controls but not in PAE offspring. GABAergic feedback inhibition of granule cell responsiveness was not affected by either PAE or methimepip. PAE reduced LTP in the DG, another effect mimicked in methimepip-treated control rats. Again, methimepip did not exacerbate the PAE-induced LTP deficit. Thus, while methimepip treatment of control rats mimicked some baseline and activity-dependent deficits observed in saline-treated PAE offspring, methimepip treatment of PAE rats did not exacerbate these deficits. Whether the absence of an added methimepip effect in PAE offspring is a consequence of a “floor effect” for the responses measured or is due to differential drug dose responsiveness will require further investigation. Further, more detailed studies of H3 receptor-mediated responses in vitro may provide clearer insights into the role of the H3 receptor regulation of excitatory transmission at the perforant path - DG synapse in PAE rats.

Moderate Prenatal Alcohol Exposure Enhances GluN2B Containing NMDA Receptor Binding and Ifenprodil Sensitivity in Rat Agranular Insular Cortex

“…At present little information exists about the role of GluN2B in synaptic plasticity in frontal cortex, however, the available data from other circuits suggest that the increased GluN2B expression observed in this study following PAE should facilitate LTP. This prediction stands in contrast to the LTP deficits observed in perforant path-dentate gyrus synapses following moderate PAE [ 120 , 121 ]. This potential double dissociation, between the effects of PAE exposure on AID and hippocampal synaptic circuits with regard to GluN2B subunit expression, requires evaluation in future studies.…”

Function and Mechanism of Myelin Regulation in Alcohol Abuse and Alcoholism

“…Given that choline is abundant in myelin, it is possible that this restorative effect may involve myelination. Antihistamines were shown to blunt deficits of prenatal EtOH on hippocampal function, and enhance myelin formation after social isolation, providing another attractive therapeutic approach. This is an important but still underexplored research field.…”

TRPC6-mediated ERK1/2 Activation Regulates Neuronal Excitability via Subcellular Kv4.3 Localization in the Rat Hippocampus

“…In the present study, TRPC6 knockdown increased the excitability ratio in DGC accompanied by reduced membrane Kv4.3 localization and the responsiveness to 4-AP. Since the excitability ratio is not relevant to paired-pulse inhibition of DGC (Varaschin et al, 2014 ), the increased excitability ratio may be an indicative of the changed intrinsic electrical properties of DGC resulting in the lowered action potential threshold independent of GABAergic inhibition. Furthermore, the reduction in Kv4.3 expression decreases the sensitivity to 4-AP (Gao et al, 2010 ).…”