TY - JOUR
T1 - GABAA and NMDA receptor density alterations and their behavioral correlates in the gestational methylazoxymethanol acetate model for schizophrenia
AU - Kiemes, Amanda
AU - Gomes, Felipe V.
AU - Cash, Diana
AU - Uliana, Daniela L.
AU - Simmons, Camilla
AU - Singh, Nisha
AU - Vernon, Anthony
AU - Turkheimer, Federico
AU - Davies, Cathy
AU - Stone, James
AU - Grace, Anthony A
AU - Modinos, Gemma
N1 - Funding Information:
This research was funded in part by the Wellcome Trust [Sir Henry Dale Fellowship 202397/Z/16/Z to GM]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. This work was in part supported by National Institutes of Health Grant No. MH57440 to AAG. FVG receives a Sao Paulo Research Foundation Young Investigator grant (2018/17597-3). Data from a subset of animals used in this paper had been previously analysed and published in conference abstracts (https://doi.org/ 10.1093/schbul/sbaa029.740; https://doi.org/10.1016/j.euroneuro.2021.01.014). A version of this paper can be found on the bioRxiv pre-print server (https://doi.org/ 10.1101/2021.06.21.449343).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/11/6
Y1 - 2021/11/6
N2 - Hippocampal hyperactivity driven by GABAergic interneuron deficits and NMDA receptor hypofunction is associated with the hyperdopaminergic state often observed in schizophrenia. Furthermore, previous research in the methylazoxymethanol acetate (MAM) rat model has demonstrated that repeated peripubertal diazepam administration can prevent the emergence of adult hippocampal hyperactivity, dopamine-system hyperactivity, and associated psychosis-relevant behaviors. Here, we sought to characterize hippocampal GABAA and NMDA receptors in MAM-treated rats and to elucidate the receptor mechanisms underlying the promising effects of peripubertal diazepam exposure. Quantitative receptor autoradiography was used to measure receptor density in the dorsal hippocampus CA1, ventral hippocampus CA1, and ventral subiculum. Specifically, [3H]-Ro15-4513 was used to quantify the density of α5GABAA receptors (α5GABAAR), [3H]-flumazenil to quantify α1-3;5GABAAR, and [3H]-MK801 to quantify NMDA receptors. MAM rats exhibited anxiety and schizophrenia-relevant behaviors as measured by elevated plus maze and amphetamine-induced hyperlocomotion (AIH), although diazepam only partially rescued these behaviors. α5GABAAR density was reduced in MAM-treated rats in all hippocampal sub-regions, and negatively correlated with AIH. Ventral hippocampus CA1 α5GABAAR density was positively correlated with anxiety-like behavior. Dorsal hippocampus CA1 NMDA receptor density was increased in MAM-treated rats, and positively correlated with AIH. [3H]-flumazenil revealed no significant effects. Finally, we found no significant effect of diazepam treatment on receptor densities, potentially related to the only partial rescue of schizophrenia-relevant phenotypes. Overall, our findings provide first evidence of α5GABAAR and NMDA receptor abnormalities in the MAM model, suggesting that more selective pharmacological agents may become a novel therapeutic mechanism in schizophrenia.
AB - Hippocampal hyperactivity driven by GABAergic interneuron deficits and NMDA receptor hypofunction is associated with the hyperdopaminergic state often observed in schizophrenia. Furthermore, previous research in the methylazoxymethanol acetate (MAM) rat model has demonstrated that repeated peripubertal diazepam administration can prevent the emergence of adult hippocampal hyperactivity, dopamine-system hyperactivity, and associated psychosis-relevant behaviors. Here, we sought to characterize hippocampal GABAA and NMDA receptors in MAM-treated rats and to elucidate the receptor mechanisms underlying the promising effects of peripubertal diazepam exposure. Quantitative receptor autoradiography was used to measure receptor density in the dorsal hippocampus CA1, ventral hippocampus CA1, and ventral subiculum. Specifically, [3H]-Ro15-4513 was used to quantify the density of α5GABAA receptors (α5GABAAR), [3H]-flumazenil to quantify α1-3;5GABAAR, and [3H]-MK801 to quantify NMDA receptors. MAM rats exhibited anxiety and schizophrenia-relevant behaviors as measured by elevated plus maze and amphetamine-induced hyperlocomotion (AIH), although diazepam only partially rescued these behaviors. α5GABAAR density was reduced in MAM-treated rats in all hippocampal sub-regions, and negatively correlated with AIH. Ventral hippocampus CA1 α5GABAAR density was positively correlated with anxiety-like behavior. Dorsal hippocampus CA1 NMDA receptor density was increased in MAM-treated rats, and positively correlated with AIH. [3H]-flumazenil revealed no significant effects. Finally, we found no significant effect of diazepam treatment on receptor densities, potentially related to the only partial rescue of schizophrenia-relevant phenotypes. Overall, our findings provide first evidence of α5GABAAR and NMDA receptor abnormalities in the MAM model, suggesting that more selective pharmacological agents may become a novel therapeutic mechanism in schizophrenia.
UR - http://www.scopus.com/inward/record.url?scp=85118627037&partnerID=8YFLogxK
U2 - 10.1038/s41386-021-01213-0
DO - 10.1038/s41386-021-01213-0
M3 - Article
SN - 0893-133X
VL - 47
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 3
ER -