Modeling Early Cortical Serotonergic Deficits in Autism

Overview

Journal Behav Brain Res

Specialties Neurology
Psychology
Social Sciences

Date 2006 Oct 13

PMID 17034875

Citations 31

Authors

Carolyn B Boylan

Mary E Blue

Christine F Hohmann

Affiliations

Soon will be listed here.

Abstract

Autism is a developmental brain disorder characterized by deficits in social interaction, language and behavior. Brain imaging studies demonstrate increased cerebral cortical volumes and micro- and macro-scopic neuroanatomic changes in children with this disorder. Alterations in forebrain serotonergic function may underlie the neuroanatomic and behavioral features of autism. Serotonin is involved in neuronal growth and plasticity and these actions are likely mediated via serotonergic and glutamatergic receptors. Few animal models of autism have been described that replicate both etiology and pathophysiology. We report here on a selective serotonin (5-HT) depletion model of this disorder in neonatal mice that mimics neurochemical and structural changes in cortex and, in addition, displays a behavioral phenotype consistent with autism. Newborn male and female mice were depleted of forebrain 5-HT with injections of the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), into the bilateral medial forebrain bundle (mfb). Behavioral testing of these animals as adults revealed alterations in social, sensory and stereotypic behaviors. Lesioned mice showed significantly increased cortical width. Serotonin immunocytochemistry showed a dramatic long-lasting depletion of 5-HT containing fibers in cerebral cortex until postnatal day (PND) 60. Autoradiographic binding to high affinity 5-HT transporters was significantly but transiently reduced in cerebral cortex of 5,7-DHT-depleted mice. AMPA glutamate receptor binding was decreased at PND 15. We hypothesize that increased cerebral cortical volume and sensorimotor, cognitive and social deficits observed in both 5-HT-depleted animals and in individuals with autism, may be the result of deficiencies in timely axonal pruning to key cerebral cortical areas.

Citing Articles

Robust and replicable functional brain signatures of 22q11.2 deletion syndrome and associated psychosis: a deep neural network-based multi-cohort study.

Supekar K, de Los Angeles C, Ryali S, Kushan L, Schleifer C, Repetto G Mol Psychiatry. 2024; 29(10):2951-2966.

PMID: 38605171 DOI: 10.1038/s41380-024-02495-8.

Evaluating the Potential Use of Serotonergic Psychedelics in Autism Spectrum Disorder.

Markopoulos A, Inserra A, De Gregorio D, Gobbi G Front Pharmacol. 2022; 12:749068.

PMID: 35177979 PMC: 8846292. DOI: 10.3389/fphar.2021.749068.

Biopsychological correlates of repetitive and restricted behaviors in autism spectrum disorders.

Comparan-Meza M, Vargas de la Cruz I, Jauregui-Huerta F, Gonzalez-Castaneda R, Gonzalez-Perez O, Galvez-Contreras A Brain Behav. 2021; 11(10):e2341.

PMID: 34472728 PMC: 8553330. DOI: 10.1002/brb3.2341.

Comparison of the effects of perceptual-motor exercises, vitamin D supplementation and the combination of these interventions on decreasing stereotypical behavior in children with autism disorder.

Moradi H, Sohrabi M, Taheri H, Khodashenas E, Movahedi A Int J Dev Disabil. 2021; 66(2):122-132.

PMID: 34141374 PMC: 8132924. DOI: 10.1080/20473869.2018.1502068.

Brain hyperserotonemia causes autism-relevant social deficits in mice.

Tanaka M, Sato A, Kasai S, Hagino Y, Kotajima-Murakami H, Kashii H Mol Autism. 2018; 9:60.

PMID: 30498565 PMC: 6258166. DOI: 10.1186/s13229-018-0243-3.

References

Bennett-Clarke C, Hankin M, Leslie M, Chiaia N, Rhoades R . Patterning of the neocortical projections from the raphe nuclei in perinatal rats: investigation of potential organizational mechanisms. J Comp Neurol. 1994; 348(2):277-90. DOI: 10.1002/cne.903480209. View

Chiaia N, Fish S, Bauer W, Figley B, Eck M, Bennett-Clarke C . Effects of postnatal blockade of cortical activity with tetrodotoxin upon the development and plasticity of vibrissa-related patterns in the somatosensory cortex of hamsters. Somatosens Mot Res. 1994; 11(3):219-28. DOI: 10.3109/08990229409051390. View

Gu Q, Singer W . Involvement of serotonin in developmental plasticity of kitten visual cortex. Eur J Neurosci. 1995; 7(6):1146-53. DOI: 10.1111/j.1460-9568.1995.tb01104.x. View

Whitaker-Azmitia P, Druse M, Walker P, Lauder J . Serotonin as a developmental signal. Behav Brain Res. 1996; 73(1-2):19-29. DOI: 10.1016/0166-4328(96)00071-x. View

Cases O, Vitalis T, Seif I, De Maeyer E, Sotelo C, Gaspar P . Lack of barrels in the somatosensory cortex of monoamine oxidase A-deficient mice: role of a serotonin excess during the critical period. Neuron. 1996; 16(2):297-307. DOI: 10.1016/s0896-6273(00)80048-3. View

Leary M, Hill D . Moving on: autism and movement disturbance. Ment Retard. 1996; 34(1):39-53. View

Roullet P, Mele A, Ammassari-Teule M . Involvement of glutamatergic and dopaminergic systems in the reactivity of mice to spatial and non-spatial change. Psychopharmacology (Berl). 1996; 126(1):55-61. DOI: 10.1007/BF02246411. View

Bennett-Clarke C, Chiaia N, Rhoades R . Thalamocortical afferents in rat transiently express high-affinity serotonin uptake sites. Brain Res. 1996; 733(2):301-6. DOI: 10.1016/0006-8993(96)00791-3. View

Levitt J, Blanton R, Smalley S, Thompson P, Guthrie D, McCracken J . Cortical sulcal maps in autism. Cereb Cortex. 2003; 13(7):728-35. DOI: 10.1093/cercor/13.7.728. View

10.

Courchesne E, Carper R, Akshoomoff N . Evidence of brain overgrowth in the first year of life in autism. JAMA. 2003; 290(3):337-44. DOI: 10.1001/jama.290.3.337. View

11.

Gage N, Siegel B, Roberts T . Cortical auditory system maturational abnormalities in children with autism disorder: an MEG investigation. Brain Res Dev Brain Res. 2003; 144(2):201-9. DOI: 10.1016/s0165-3806(03)00172-x. View

12.

Muller R, Kleinhans N, Kemmotsu N, Pierce K, Courchesne E . Abnormal variability and distribution of functional maps in autism: an FMRI study of visuomotor learning. Am J Psychiatry. 2003; 160(10):1847-62. DOI: 10.1176/appi.ajp.160.10.1847. View

13.

Djavadian R, Wielkopolska E, Turlejski K . Neonatal depletion of serotonin increases the numbers of callosally projecting neurons in cat visual areas 17 and 18. Neurosci Lett. 2003; 351(2):91-4. DOI: 10.1016/j.neulet.2003.07.008. View

14.

Dickson K, Kind P . NMDA receptors: neural map designers and refiners?. Curr Biol. 2003; 13(23):R920-2. DOI: 10.1016/j.cub.2003.11.015. View

15.

Barnea-Goraly N, Kwon H, Menon V, Eliez S, Lotspeich L, Reiss A . White matter structure in autism: preliminary evidence from diffusion tensor imaging. Biol Psychiatry. 2004; 55(3):323-6. DOI: 10.1016/j.biopsych.2003.10.022. View

16.

Herbert M, Ziegler D, Makris N, Filipek P, Kemper T, Normandin J . Localization of white matter volume increase in autism and developmental language disorder. Ann Neurol. 2004; 55(4):530-40. DOI: 10.1002/ana.20032. View

17.

Akshoomoff N, Lord C, Lincoln A, Courchesne R, Carper R, Townsend J . Outcome classification of preschool children with autism spectrum disorders using MRI brain measures. J Am Acad Child Adolesc Psychiatry. 2004; 43(3):349-57. DOI: 10.1097/00004583-200403000-00018. View

18.

Muhle R, Trentacoste S, Rapin I . The genetics of autism. Pediatrics. 2004; 113(5):e472-86. DOI: 10.1542/peds.113.5.e472. View

19.

Connell S, Karikari C, Hohmann C . Sex-specific development of cortical monoamine levels in mouse. Brain Res Dev Brain Res. 2004; 151(1-2):187-91. DOI: 10.1016/j.devbrainres.2004.03.008. View

20.

Courchesne E . Brain development in autism: early overgrowth followed by premature arrest of growth. Ment Retard Dev Disabil Res Rev. 2004; 10(2):106-11. DOI: 10.1002/mrdd.20020. View