Reversal of Prenatal Alcohol-induced Deficits in Long-term Potentiation by the Histamine H3 Inverse Agonist SAR153954
Cognitive impairments are common consequences of Fetal Alcohol Spectrum Disorder (FASD). The hippocampus is susceptible to the effects of prenatal alcohol exposure (PAE) which persist throughout an individual’s life. Previous studies have identified deficits in long-term potentiation (LTP) in perforant pathway to dentate gyrus synapses as an adverse consequence of PAE. Although there have been numerous investigations, PAE-induced deficits in synaptic plasticity remain poorly understood. Currently, there are no known, clinically effective pharmacotherapeutic interventions for these deficits. This study investigated the effects of PAE on LTP in the dentate gyrus and the H3 receptor inverse agonist, SAR152954, as a candidate to reverse deficits in LTP associated with PAE. We utilized a rat model of moderate PAE (60 mg/dl peak blood alcohol content). Urethane-anesthetized adult male Long-Evans rats (N=36; PAE = 18) were implanted with monopolar electrodes in the dorsal dentate gyrus and in the entorhinal cortical perforant pathway. Evoked responses were recorded at 20KHz (Stimuli: 100 μs, 1/30s, 400 μA). An Input-Output (I/O) curve (50-500 μA) was obtained to determine the EC40 (40% of maximal response). Rats were given a single injection of SAR152954 (1.0 mg/kg) or saline (vehicle) 30 min prior to the recording session. Baseline recordings were obtained for 20 min. Synaptic potentiation was induced by 5 trains of high frequency stimulation (HFS; 400Hz, 25ms duration) with 30s inter-train intervals. Post-HFS recordings were obtained for 60 min. Fractional change of the post-HFS fEPSP relative to baseline was calculated for 1 min intervals. PAE rats displayed reduced LTP relative to controls (p = 0.026).
PAE rats receiving SAR152954 reversed PAE-induced deficits to levels comparable to the control animals (p > .8) and greater than PAE animals that received the vehicle (p = 0.046). These results indicate that the H3 receptor inverse agonist SAR152954, reverses PAE-induced deficits in LTP and offer a possibility for investigating agents with this mechanism of action as novel pharmacological interventions for FASD-associated cognitive impairments.
Goncalves-Garcia, Monica; Suzy Davies; Daniel D. Savage; and Derek A. Hamilton. "Reversal of Prenatal Alcohol-induced Deficits in Long-term Potentiation by the Histamine H3 Inverse Agonist SAR153954." (2021). https://digitalrepository.unm.edu/hsc-bbhrd/39
Poster presented at the Brain & Behavioral Health Research Day 2021
Support from:Sanofi Pharmaceutical for the generous donation of SAR152954, NCATS 1UH2 TR0022082, NIAAA P50 AA22534,New Mexico Alcohol Research Center (NMARC).