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Tandospirone, a partial 5-HT1A receptor agonist, administered systemically or into anterior cingulate attenuates repetitive behaviors in Shank3B mice.
Int J Neuropsychopharmacol. 2020 Jul 03 [Online ahead of print]IJ

Abstract

BACKGROUND

Several cases of autism spectrum disorder (ASD) have been linked to mutations in the SHANK3 gene. Haploinsufficiency of the SHANK3 gene contributes to Phelan-McDermid syndrome, which often presents an ASD phenotype along with moderate to severe intellectual disability. A SHANK3 gene deletion in mice results in elevated excitation of cortical pyramidal neurons that alters signaling to other brain areas. Serotonin 1A receptors (5HT1ARs) are highly expressed on layer 2 cortical neurons and are known to have inhibitory actions. 5HT1AR agonist treatment in autistic cases with SHANK3 mutations and possibly other cases may restore excitatory and inhibitory balance that attenuates core symptoms.

METHODS

A series of experiments investigated the effects of acute tandospirone treatment on spatial learning and self-grooming; subchronic treatment of tandospirone on self-grooming behavior and the effect of tandospirone infusion into the anterior cingulate on self-grooming behavior.

RESULTS

Only male Shank3B+/- mice exhibited a spatial learning deficit and elevated self-grooming. Acute intraperitoneal injection of tandospirone, 0.01 and 0.06 mg/kg in male Shank3B+/- mice, attenuated a spatial acquisition deficit by improving sensitivity to positive reinforcement and reduced elevated self-grooming behavior. Repeated tandospirone (0.06 mg/kg) treatment attenuated elevated self-grooming behavior in male Shank3B+/- mice. Tandospirone injected into the anterior cingulate/premotor area reduced self-grooming behavior in male Shank3B+/- mice.

CONCLUSIONS

These results suggest that stimulation of cortical 5HT1ARs may reduce repetitive behaviors and cognitive impairments as observed in ASD possibly by attenuating an excitation/inhibition imbalance. Further, tandospirone may serve as a treatment in ASD and other disorders associated with SHANK3 mutations.

Authors+Show Affiliations

Department of Psychology, University of Illinois at Chicago, Chicago, IL.Department of Psychology, University of Illinois at Chicago, Chicago, IL.Department of Psychology, University of Illinois at Chicago, Chicago, IL.Department of Psychology, University of Illinois at Chicago, Chicago, IL.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32619232

Citation

Dunn, Jeffrey T., et al. "Tandospirone, a Partial 5-HT1A Receptor Agonist, Administered Systemically or Into Anterior Cingulate Attenuates Repetitive Behaviors in Shank3B Mice." The International Journal of Neuropsychopharmacology, 2020.
Dunn JT, Mroczek J, Patel HR, et al. Tandospirone, a partial 5-HT1A receptor agonist, administered systemically or into anterior cingulate attenuates repetitive behaviors in Shank3B mice. Int J Neuropsychopharmacol. 2020.
Dunn, J. T., Mroczek, J., Patel, H. R., & Ragozzino, M. E. (2020). Tandospirone, a partial 5-HT1A receptor agonist, administered systemically or into anterior cingulate attenuates repetitive behaviors in Shank3B mice. The International Journal of Neuropsychopharmacology. https://doi.org/10.1093/ijnp/pyaa047
Dunn JT, et al. Tandospirone, a Partial 5-HT1A Receptor Agonist, Administered Systemically or Into Anterior Cingulate Attenuates Repetitive Behaviors in Shank3B Mice. Int J Neuropsychopharmacol. 2020 Jul 3; PubMed PMID: 32619232.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tandospirone, a partial 5-HT1A receptor agonist, administered systemically or into anterior cingulate attenuates repetitive behaviors in Shank3B mice. AU - Dunn,Jeffrey T, AU - Mroczek,Jessica, AU - Patel,Harsh R, AU - Ragozzino,Michael E, Y1 - 2020/07/03/ PY - 2020/02/21/received PY - 2020/7/4/entrez PY - 2020/7/4/pubmed PY - 2020/7/4/medline KW - 5-HT1A receptor KW - Shank3 KW - autism KW - learning KW - repetitive behaviors KW - tandospirone JF - The international journal of neuropsychopharmacology JO - Int. J. Neuropsychopharmacol. N2 - BACKGROUND: Several cases of autism spectrum disorder (ASD) have been linked to mutations in the SHANK3 gene. Haploinsufficiency of the SHANK3 gene contributes to Phelan-McDermid syndrome, which often presents an ASD phenotype along with moderate to severe intellectual disability. A SHANK3 gene deletion in mice results in elevated excitation of cortical pyramidal neurons that alters signaling to other brain areas. Serotonin 1A receptors (5HT1ARs) are highly expressed on layer 2 cortical neurons and are known to have inhibitory actions. 5HT1AR agonist treatment in autistic cases with SHANK3 mutations and possibly other cases may restore excitatory and inhibitory balance that attenuates core symptoms. METHODS: A series of experiments investigated the effects of acute tandospirone treatment on spatial learning and self-grooming; subchronic treatment of tandospirone on self-grooming behavior and the effect of tandospirone infusion into the anterior cingulate on self-grooming behavior. RESULTS: Only male Shank3B+/- mice exhibited a spatial learning deficit and elevated self-grooming. Acute intraperitoneal injection of tandospirone, 0.01 and 0.06 mg/kg in male Shank3B+/- mice, attenuated a spatial acquisition deficit by improving sensitivity to positive reinforcement and reduced elevated self-grooming behavior. Repeated tandospirone (0.06 mg/kg) treatment attenuated elevated self-grooming behavior in male Shank3B+/- mice. Tandospirone injected into the anterior cingulate/premotor area reduced self-grooming behavior in male Shank3B+/- mice. CONCLUSIONS: These results suggest that stimulation of cortical 5HT1ARs may reduce repetitive behaviors and cognitive impairments as observed in ASD possibly by attenuating an excitation/inhibition imbalance. Further, tandospirone may serve as a treatment in ASD and other disorders associated with SHANK3 mutations. SN - 1469-5111 UR - https://www.unboundmedicine.com/medline/citation/32619232/Tandospirone,_a_partial_5-HT1A_receptor_agonist,_administered_systemically_or_into_anterior_cingulate_attenuates_repetitive_behaviors_in_Shank3B_mice L2 - https://academic.oup.com/ijnp/article-lookup/doi/10.1093/ijnp/pyaa047 DB - PRIME DP - Unbound Medicine ER -
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