Prenatal Alcohol Exposure Increases Histamine H<sub>3</sub> Receptor‐Mediated Inhibition of Glutamatergic Neurotransmission in Rat Dentate Gyrus

Varaschin, Rafael K.; Allen, Nyika A.; Rosenberg, Martina; Valenzuela, C. Fernando; Savage, Daniel D.

doi:10.1111/acer.13574

Cited by 12 publications

(16 citation statements)

References 58 publications

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“…Rate remapping by CA3 place cells, which was reduced in the present study, is dependent on the integrity of synaptic plasticity and NMDA receptor function at perforant pathway synapses [37]. Previous studies have also reported that moderate PAE can reduce mGluR5 receptor function in the dentate gyrus [85] and leads to elevated histamine H3-receptor-mediated inhibition of glutamate release from perforant path nerve terminals [86]. Likewise, the integrity of input from the entorhinal cortex, which forms the most prominent source of perforant path axons, is critical for place cell activity [87], and damage to entorhinal cortical cells can produce a similar loss of place field stability and reduction in spatial tuning [88][89][90].…”

Section: Discussionsupporting

confidence: 57%

Altered Hippocampal Place Cell Representation and Theta Rhythmicity following Moderate Prenatal Alcohol Exposure

et al. 2020

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Prenatal alcohol exposure (PAE) leads to profound deficits in spatial memory and synaptic and cellular alterations to the hippocampus that last into adulthood. Neurons in the hippocampus called place cells discharge as an animal enters specific places in an environment, establish distinct ensemble codes for familiar and novel places, and are modulated by local theta rhythms. Spatial memory is thought to critically depend on the integrity of hippocampal place cell firing. Therefore, we tested the hypothesis that hippocampal place cell firing is impaired after PAE by performing in vivo recordings from the hippocampi (CA1 and CA3) of moderate PAE and control adult rats. Our results show that hippocampal CA3 neurons from PAE rats have reduced spatial tuning. Second, CA1 and CA3 neurons from PAE rats are less likely to orthogonalize their firing between directions of travel on a linear track and between changes in contextual stimuli in an open arena compared to control neurons. Lastly, reductions in the number of hippocampal place cells exhibiting significant theta rhythmicity and phase precession were observed, which may suggest changes to hippocampal microcircuit function. Together, the reduced spatial tuning and sensitivity to contextual changes provide a neural systems-level mechanism to explain spatial memory impairment after moderate PAE. In BriefHarvey et al. demonstrate that prenatal alcohol exposure disrupts hippocampal place cell firing and slows theta oscillations. The findings represent a critical step in developing a complete multi-level

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Section: Discussionsupporting

confidence: 57%

Altered Hippocampal Place Cell Representation and Theta Rhythmicity following Moderate Prenatal Alcohol Exposure

et al. 2020

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“…PAE is associated with widespread abnormalities in brain structure and function. Among these are changes to white matter integrity (Wozniak et al, 2011), cortical thickness (Yang et al, 2012), receptor expression (Galindo et al, 2004), neurotransmission (Varaschin et al, 2018), long-term potentiation (Sutherland et al, 1997), and structural synaptic plasticity (Rice et al, 2012), which could potentially explain changes in network properties, but are not accessible in the present investigation. Measures of path length and global efficiency have also been associated with genetic heritability (van den Heuvel et al, 2013, Fornito et al, 2011, and PAE is known to influence multiple epigenetic mechanisms that affect brain development (Lussier et al, 2017), which represent additional routes by which PAE can alter network characteristics.…”

Section: Global Measures Of Network Modularity Have Not Been Previouslymentioning

confidence: 91%

Disruptions in global network segregation and integration in adolescents and young adults with fetal alcohol spectrum disorder

Rodríguez

Vergara

Calhoun

et al. 2021

Alcoholism Clin & Exp Res

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Background: Fetal alcohol spectrum disorder (FASD) is a significant public health problem that is associated with a broad range of physical, neurocognitive, and behavioral effects resulting from prenatal alcohol exposure (PAE). Magnetic resonance imaging (MRI) has been an important tool for advancing our knowledge of abnormal brain structure and function in individuals with FASD. However, whereas only a small number of studies have applied graph theory-based network analysis to resting-state functional MRI (fMRI) data in individuals with FASD additional research in this area is needed. Methods: Resting-state fMRI data were collected from adolescent and young adult participants (ages 12-22) with fetal alcohol syndrome (FAS) or alcohol-related neurodevelopmental disorder (ARND) and neurotypically developing controls (CNTRL) from previous studies. Group independent components analysis (gICA) was applied to fMRI data to extract components representing functional brain networks. Functional network connectivity (FNC), measured by Pearson correlation of the average independent component (IC) time series, was analyzed under a graph theory framework to compare network modularity, the average clustering coefficient, characteristic path length, and global efficiency between groups. Cognitive intelligence, measured by the Wechsler Abbreviated Scale of Intelligence (WASI), was compared and correlated to global network measures.Results: Group comparisons revealed significant differences in the average clustering coefficient, characteristic path length, and global efficiency. Modularity was not significantly different between groups. The FAS and ARND groups scored significantly lower than the CNTRL group on Full Scale IQ (FS-IQ) and the Vocabulary subtest, but not the Matrix Reasoning subtest. No significant associations between intelligence and graph theory measures were detected. Conclusion:Our results partially agree with previous studies examining global graph theory metrics in children and adolescents with FASD and suggest that the exposure to alcohol during prenatal development leads to disruptions in aspects of functional network segregation and integration.

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“…Radio-histochemical studies employing the selective H3R antagonist [ 3 H]-A349821 indicated that moderate PAE did not affect H3R density in any brain region measured ( Varaschin et al, 2018 ). However, using the selective H3R agonist methimepip to stimulate [ 35 S]-GTPγS (GTP) binding as a measure of H3R receptor-effector coupling, we observed a significant enhancement of GTP binding in hippocampal and cerebrocortical regions of PAE rats, particularly at higher agonist concentrations ( Varaschin et al, 2018 ). The functional significance of this heightened H3 receptor-effector coupling response in PAE rats was examined in dentate gyrus slices.…”

Section: Introductionmentioning

confidence: 99%

“…The functional significance of this heightened H3 receptor-effector coupling response in PAE rats was examined in dentate gyrus slices. The ability of methimepip to decrease the probability of glutamate release from dentate gyrus slices, noted as an increase in the paired-pulse ratio measure, was significantly elevated in PAE rats ( Varaschin et al, 2018 ). Further, the concentrations of methimepip that lowered the probability of glutamate release were similar to the methimepip concentrations that enhanced GTP binding in dentate gyrus of PAE rats.…”

Section: Introductionmentioning

confidence: 99%

Effect of moderate prenatal ethanol exposure on the differential expression of two histamine H3 receptor isoforms in different brain regions of adult rat offspring

Davies,

Lujan,

Rappaport

et al. 2023

Front. Neurosci.

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We have reported that prenatal alcohol exposure (PAE) elevates histamine H3 receptor (H3R) agonist-mediated inhibition of glutamatergic neurotransmission in the dentate gyrus. Here, we hypothesized that PAE alters the expression of two prominent H3R isoforms namely, the rH3A and rH3C isoforms, which have differing intrinsic activities for H3R agonists, in a manner that may contribute to heightened H3R function in PAE rats. In contrast to our predictions, we found different effects of sex and PAE in various brain regions with significant interactions between sex and PAE in dentate gyrus and entorhinal cortex for both isoforms. Subsequently, to confirm the PAE-and sex-induced differences on H3R isoform mRNA expression, we developed a polyclonal antibody selective for the rH3A inform. Western blots of rH3A mRNA-transfected HEK-293 cells identified a ~ 48 kDa band of binding consistent with the molecular weight of rH3A, thus confirming antibody sensitivity for rH3A protein. In parallel, we also established a pan-H3R knockout mice line to confirm antibody specificity in rodent brain membranes. Both qRT-PCR and H3R agonist-stimulated [35S]-GTPγS binding confirmed the absence of mH3A mRNA and H3 receptor-effector coupling in H3R knockout (KO) mice. Subsequent western blotting studies in both rat and mouse brain membranes were unable to detect rH3A antibody binding at ~48 kDa. Rather, the H3RA antibody bound to a ~ 55 kDa band in both rat and mouse membranes, including H3R KO mice, suggesting H3RA binding was not specific for H3Rs in rodent membranes. Subsequent LC/MS analysis of the ~55 kDa band in frontal cortical membranes identified the highly abundant beta subunit of ATPase in both WT and KO mice. Finally, LC/MS analysis of the ~48 kDa band from rH3A mRNA-transfected HEK-293 cell membranes was able to detect rH3A protein, but its presence was below the limits of quantitative reliability. We conclude that PAE alters rH3A and rH3C mRNA expression in some of the same brain regions where we have previously reported PAE-induced alterations in H3R-effector coupling. However, interpreting the functional consequences of altered H3R isoform expression was limited given the technical challenges of measuring the relatively low abundance of rH3A protein in native membrane preparations.

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Prenatal Alcohol Exposure Increases Histamine H₃ Receptor‐Mediated Inhibition of Glutamatergic Neurotransmission in Rat Dentate Gyrus

Cited by 12 publications

References 58 publications

Altered Hippocampal Place Cell Representation and Theta Rhythmicity following Moderate Prenatal Alcohol Exposure

Altered Hippocampal Place Cell Representation and Theta Rhythmicity following Moderate Prenatal Alcohol Exposure

Disruptions in global network segregation and integration in adolescents and young adults with fetal alcohol spectrum disorder

Effect of moderate prenatal ethanol exposure on the differential expression of two histamine H3 receptor isoforms in different brain regions of adult rat offspring

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Prenatal Alcohol Exposure Increases Histamine H3 Receptor‐Mediated Inhibition of Glutamatergic Neurotransmission in Rat Dentate Gyrus

Cited by 12 publications

References 58 publications

Altered Hippocampal Place Cell Representation and Theta Rhythmicity following Moderate Prenatal Alcohol Exposure

Altered Hippocampal Place Cell Representation and Theta Rhythmicity following Moderate Prenatal Alcohol Exposure

Disruptions in global network segregation and integration in adolescents and young adults with fetal alcohol spectrum disorder

Effect of moderate prenatal ethanol exposure on the differential expression of two histamine H3 receptor isoforms in different brain regions of adult rat offspring

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Prenatal Alcohol Exposure Increases Histamine H₃ Receptor‐Mediated Inhibition of Glutamatergic Neurotransmission in Rat Dentate Gyrus