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Deficits of Hippocampal RNA Editing and Social Interaction Resulting from Prenatal Stress Are Mitigated by Clozapine

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Deficits of Hippocampal RNA Editing and Social Interaction Resulting from Prenatal Stress Are Mitigated by Clozapine bioRxiv preprint doi: https://doi.org/10.1101/2021.02.02.429408; this version posted February 2, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Deficits of Hippocampal RNA Editing and Social Interaction Resulting from Prenatal 2 Stress are Mitigated by Clozapine. 3 Greg C. Bristow D.Phil.1*, Erbo Dong, Ph.D.2*, Evelyn Nwabuisi-Heath Ph.D.3*, Saverio 4 Gentile Ph.D.4, Alessandro Guidotti M.D.2 and Monsheel Sodhi Ph.D. 4#. 5 *these authors contributed equally to this work. 6 7 1. Department of Pharmacology, Bradford University, Bradford, United Kingdom. 8 2. Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60613. 9 3. Center for Biomolecular Sciences, University of Illinois at Chicago, Chicago, IL 10 60613. 11 4. Department of Molecular Pharmacology and Neuroscience, Stritch School of 12 Medicine, Loyola University Chicago, Maywood, IL. 60153. 13 14 #Correspondence to: Monsheel Sodhi Ph.D. 15 Department of Molecular Pharmacology and Neuroscience 16 Loyola University Chicago, 17 2160 S 1st Ave CTRE 424, 18 Maywood IL 60153. 19 Email: [email protected] 20 21 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.02.02.429408; this version posted February 2, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 22 Abstract 23 Background: Neurodevelopmental deficits resulting from prenatal stress are associated with 24 neurological disorders that include deficits of social behavior, such as schizophrenia 1 and 25 autism 2-7. Studies of human brain and animal models indicate that an epitranscriptomic 26 process known as ‘RNA editing’ contributes to the pathophysiology of these disorders, which 27 occur more frequently in males than in females8-20. RNA editing plays an important role in 28 brain development through its modification of excitatory and inhibitory neurotransmission 21. 29 Methods: We exposed pregnant mice to restraint stress three times daily during gestational 30 weeks 2 and 3. We treated the adult male offspring with haloperidol (1mg/kg), clozapine 31 (5mg/kg) or saline twice daily for 5 days. Subsequently we measured social interaction 32 behavior (SI) and locomotor activity, followed by next-generation sequencing analyses of 33 hippocampal RNA editing. 34 Results: Mice exposed to PRS exhibited reduced SI, which correlated with hippocampal RNA 35 editing of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits 36 GluA2, GluA3 and GluA4, the potassium channel Kv1.1, the calcium channel subunit Cav1.3, 37 calcium-dependent secretion activator (CAPS-1) and the calcium-dependent cell adhesion 38 protein, cadherin 22 (CDH22). Treatment with clozapine, but not haloperidol, normalized SI 39 behavior, and selectively reduced the deficits in GluA2 RNA editing in PRS mice. 40 Conclusions: RNA editing may contribute to impaired hippocampal function after exposure 41 to PRS. The efficacy of clozapine in improving SI behavior may include indirect stimulation of 42 GluA2 RNA editing in the hippocampus. Although these data are from male mice and not 43 humans, the results suggest a new molecular pathway by which PRS leads to life-long 44 impairments of hippocampal function. 45 2 bioRxiv preprint doi: https://doi.org/10.1101/2021.02.02.429408; this version posted February 2, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 46 Introduction 47 Psychological distress during pregnancy impairs brain development of the fetus, and there is 48 a knowledge gap about how prenatal stress increases the risk for neurodevelopmental 49 illnesses that include social and cognitive deficits, including schizophrenia (SCZ) and autism 50 spectrum disorders (ASD)22, 23, 2-7. Studies in mice show that exposure of pregnant dams to 51 restraint stress leads to sex-dependent effects on brain development24 within brain regions 52 that are sexually dimorphic, including the hippocampus. Prenatal restraint stress (PRS) 53 induces molecular pathways leading to structural deficits in the development of the 54 hippocampus25-31. We have a limited understanding of the molecular mechanisms underlying 55 the effects of PRS on hippocampal function32-37. Recent studies indicate that an 56 epitranscriptomic process called ‘RNA editing’ may play an important role in brain 57 development and psychiatric disorders associated with stress 8-21, 38-44. 58 59 RNA editing alters RNA sequence with a profound impact on the structure and function of 60 glutamate, 5-hydroxytryptamine (5-HT) and γ-aminobutyric acid (GABA) receptors in addition 61 to ion channels (illustrated in Figure 1). Accumulating data, including our own, show that RNA 62 editing plays a role in behaviors associated with anxiety 45-47 and helplessness in mice 48. 63 PRS disrupts glutamatergic transmission in the hippocampus, which leads to anxiety-like 64 behavior and social memory deficits in males 49 but not females 50. Abnormalities in the 65 hippocampus that are associated with SCZ may arise due to PRS 1 and altered regulation of 66 the glutamate system 24. 67 68 In the current study, we have tested the hypothesis that RNA editing is associated with the 69 social interaction deficits resulting from PRS in male mice, and the improvement of these 3 bioRxiv preprint doi: https://doi.org/10.1101/2021.02.02.429408; this version posted February 2, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 70 behaviors by antipsychotic treatment. We report reduced RNA editing of several proteins 71 involved in calcium homeostasis and glutamatergic transmission in the hippocampus of mice 72 exposed to PRS. RNA editing of these and additional proteins correlated with SI behavior. In 73 addition, clozapine treatment mitigated the behavioral deficits observed in PRS mice. Of the 74 molecular deficits observed in PRS mice, clozapine only mitigated deficits in GluA2 RNA 75 editing in the hippocampus. These data indicate that upregulation of GluA2 RNA editing in 76 the hippocampus may eliminate social withdrawal behavior associated with PRS. Therefore, 77 modulating GluA2 RNA editing may have the potential to improve social cognition, which is a 78 debilitating component of several psychiatric disorders, including SCZ 51. 4 bioRxiv preprint doi: https://doi.org/10.1101/2021.02.02.429408; this version posted February 2, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 79 Materials and Methods 80 Animals and PRS Procedure 81 All procedures were performed according to NIH guidelines for animal research (Guide for 82 the Care & Use of Laboratory Animals, NRC, 1996) and approved by the Animal Care 83 Committee of the University of Illinois at Chicago and Loyola University Chicago. Pregnant 84 mice (Swiss albino ND4, Harlan, Indianapolis, IN) were individually housed with a 12-h light- 85 dark cycle and access to food and water ad libitum. Control dams were left undisturbed 86 throughout gestation, while stressed dams were subjected to repeated episodes of restraint 87 stress, as described previously 52. The stress procedure (PRS) consisted of restraining 88 pregnant dams in a transparent tube (12 × 3 cm) under bright light for 45 minutes three times 89 daily from day 7 of pregnancy until delivery. After weaning (postnatal day/ PND 21), male 90 offspring were housed by condition in groups of 4-5 per cage. 91 Drug Treatment 92 Haloperidol (Sigma, St Louis, MO) and clozapine (Novartis Pharmaceuticals, Basel, 93 Switzerland) were dissolved in glacial acetic acid brought to pH 6 with the addition of sodium 94 hydroxide (NaOH, Sigma). Haloperidol (1mg/kg), clozapine (5mg/kg) and saline (vehicle/ veh) 95 were injected subcutaneously twice daily in PRS and non-stressed (NS) control mice from 96 PND 70 for 5 days. Behavioral testing of mice began 16 hours after the final injection. We 97 tested locomotor activity, followed by SI, on consecutive days. 98 Social Interaction (SI) Behavior 99 We used the “Three-Chambered Apparatus” method to measure SI 53-55. The apparatus is a 100 transparent box with three chambers, each measuring 20cm×40.5cm×22cm. Openings in the 5 bioRxiv preprint doi: https://doi.org/10.1101/2021.02.02.429408; this version posted February 2, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 101 central chamber walls (10cm×5cm) allowed access to the side chambers, which contained 102 identical wire cups, one enclosing a stranger (novel) mouse and while the other was empty. 103 Initially the test mouse was allowed to freely explore the empty apparatus for 5 min. The 104 mouse was then confined in the central chamber and a stranger mouse was placed in the 105 wire cup of one side chamber. The test was initiated by allowing the test mouse to explore all 106 three chambers freely for 10 min. SI was defined as the ratio of the sniffing time at the empty 107 cup vs. the cup enclosing the stranger mouse. Between tests the apparatus was thoroughly 108 washed with 70% ethanol and distilled water. Tests were performed under dim lighting 109 between 10am and 3pm, with sessions recorded for data analysis. Inter-rater reliability was 110 assessed by correlating the scores of two raters. 111 Locomotor activity 112 We assessed if changes in SI could be confounded by locomotor activity. We used a 113 computerized system with VersaMax software (AccuScan Instruments, Columbus, OH) to 114 quantify and track locomotor activity in mice, as described previously 56.
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