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Serotonin 5-HT1B receptor-mediated behavior and binding in mice with the overactive and dysregulated serotonin transporter Ala56 variant

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Abstract

Rationale

Elevated whole-blood serotonin (5-HT) is a robust biomarker in ~ 30% of patients with autism spectrum disorders, in which repetitive behavior is a core symptom. Furthermore, elevated whole-blood 5-HT has also been described in patients with pediatric obsessive-compulsive disorder. The 5-HT1B receptor is associated with repetitive behaviors seen in both disorders. Chronic blockade of serotonin transporter (SERT) reduces 5-HT1B receptor levels in the orbitofrontal cortex (OFC) and attenuates the sensorimotor deficits and hyperactivity seen with the 5-HT1B agonist RU24969. We hypothesized that enhanced SERT function would increase 5-HT1B receptor levels in OFC and enhance sensorimotor deficits and hyperactivity induced by RU24969.

Objectives

We examined the impact of the SERT Ala56 mutation, which leads to enhanced SERT function, on 5-HT1B receptor binding and 5-HT1B-mediated sensorimotor deficits.

Methods

Specific binding to 5-HT1B receptors was measured in OFC and striatum of naïve SERT Ala56 or wild-type mice. The impact of the 5-HT1A/1B receptor agonist RU24969 on prepulse inhibition (PPI) of startle, hyperactivity, and expression of cFos was examined.

Results

While enhanced SERT function increased 5-HT1B receptor levels in OFC of Ala56 mice, RU24969-induced PPI deficits and hyperlocomotion were not different between genotypes. Baseline levels of cFos expression were not different between groups. RU24969 increased cFos expression in OFC of wild-types and decreased cFos in the striatum.

Conclusions

While reducing 5-HT1B receptors may attenuate sensorimotor gating deficits, increased 5-HT1B levels in SERT Ala56 mice do not necessarily exacerbate these deficits, potentially due to compensations during neural circuit development in this model system.

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Funding

This work was supported by National Institutes of Health grants MH094604 (JV), MH081066 (JV), MH114296 (SA, JV), and T32MH016434 (JV/LCS).

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Authors and Affiliations

  1. Department of Psychiatry, New York State Psychiatric Institute, Columbia University, 1051 Riverside Dr., Unit 78, New York, NY, 10032, USA

    Kally C. O’Reilly, Lauren C. Shuffrey & Jeremy Veenstra-VanderWeele

  2. Department of Neurosurgery, Washington University in St. Louis, St. Louis, MO, 63110, USA

    Michelle Connor

  3. Vanderbilt University, Nashville, TN, 37232, USA

    Michelle Connor & Jeremy Veenstra-VanderWeele

  4. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, 15219, USA

    Jamie Pierson & Susanne E. Ahmari

  5. Brain Institute and Department of Biomedical Science, Florida Atlantic University, Jupiter, FL, 33458, USA

    Randy D. Blakely

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  1. Kally C. O’Reilly
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  2. Michelle Connor
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Correspondence to Jeremy Veenstra-VanderWeele.

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Conflict of interest

JV has consulted or served on advisory boards for Novartis, Roche Pharmaceuticals, and SynapDx; has received research funding from Novartis, Roche Pharmaceuticals, Forest, Seaside Therapeutics, Janssen, and SynapDx; and has received an editorial stipend from Springer and Wiley. All other authors declare that they have no competing interests.

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Supplemental File 1

Locations of 5-HT1B binding measurements. a) Contours are shown that depict where optical density readings were taken in the orbitofrontal cortex and the striatum. b) and c) Specific binding was calculated as the total binding (left) - the nonspecific binding (right) in b) wild-type and c) Ala56 mice. LO = lateral orbitofrontal cortex. VO = ventral orbitofrontal cortex, MO = medial orbitofrontal cortex, dSTR = dorsal striatum (PNG 1523 kb)

High resolution image (TIF 11169 kb)

Supplemental File 2

Table of statistics for effect of section within each hemisphere, effect of hemisphere, and effect of genotype on 5-HT1B binding for each brain region (DOCX 14 kb)

Supplemental File 3

Two hours following saline or RU24969 injection, brains were collected for cFos immunostaining. RU24969 a) induced cFos expression in the ventral OFC and b) reduced cFos expression in the ventral striatum of wild-type mice (PNG 2259 kb)

High resolution image (TIF 15105 kb)

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O’Reilly, K.C., Connor, M., Pierson, J. et al. Serotonin 5-HT1B receptor-mediated behavior and binding in mice with the overactive and dysregulated serotonin transporter Ala56 variant. Psychopharmacology 238, 1111–1120 (2021). https://doi.org/10.1007/s00213-020-05758-8

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