A further support to the hypothesis of a link between serotonin, autism, and the cerebellum: Reply
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CORRESPONDENCE A Further Support to the Hypothesis of a Link between Serotonin, Autism, and the Cerebellum To the Editor: We read with much interest the paper of Pierce and Courchesne published recently in this journal where the authors reported that a group of children with autism show a decreased exploratory activity correlating significantly with the cerebellar hypoplasia of vermal lobules VI–VII, and mentioned different animal studies involving mutant mice or guinea pigs with genetic defects provoking Purkinje neuron loss (Pierce and Courchesne 2001). We would like to focus the attention on some articles of our group that may be complementary, in which we hypothesized a link between autism, cerebellum, and the serotonin (5-HT) system (Marazziti et al 1999; Pasqualetti et al 1999), on the basis of the available data and the mRNA expression of a specific 5-HT receptor subtypes (i.e., the 5A) in human brain by means of in-situ hybridization. In fact, we observed in the cerebellum a high level of 5-HT 5A mRNA expression, particularly in the Purkinje cell perikarya, but also in the granule layer and in the dentate nucleus. This pattern of mRNA expression was found in the cortex of both hemispheres and the vermis (Pasqualetti et al 1999). According to us, the wide distribution of 5-HT 5A mRNA in the cerebellum makes this receptor a putative candidate, involved in different functions and, perhaps, in cognitive and emotional processes. This hypothesis is in agreement with the observation that the 5-HT 5A mRNA is expressed in the cortex and in limbic structures, such as the hippocampus and the ventrolateral region of the amygdala, whereas it is poorly represented in basal ganglia and absent from substantia nigra, areas both involved in motor function control. When the motor control function of the cerebellum is impaired, the resulting and known effect is ataxia; we would suggest that similarly, when impaired cerebellar control of cognitive and emotional functions occurs, the result might be a sort of “cognitive” and “emotional” ataxia, as observed in autism, where subjects appear unable to coordinate these functions properly. It is noteworthy that, amongst the functions attributed to 5-HT 5A , there is a role in brain development and that reeler mutant rats exhibit abnormalities of cerebellum, cerebral cortex, hippocampus and olfactory bulbs consistent with the pattern of 5-HT 5A mRNA expression reported by us, as well as abnormal- ities of exploratory behavior (Grailhe et al 1999) in agreement with the findings reported by Pierce and Courchesne (2001). Donatella Marazziti University of Pisa Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie Via Roma, 67 56100 Pisa, Italy PII S0006-3223(02)01406-3 References Grailhe R, Waeber C, Dulawa SC, Hornung JP, Zhuang X, Brunner D, et al (1999): Increased exploratory activity and altered response to LSD in mice lacking 5-HT5 A receptor. Neuron 22:5981–5991. Marazziti D, Nardi I, Cassano GB (1999): Autism, serotonin and cerebellum: Might there be a connection? CNS Spectrums 3:80 –82. Pasqualetti M, Ori M, Nardi I, Cassano GB, Castagna A, Marazziti D (1999): Distribution of serotonin 5A receptors in human brain. Mol Brain Res 56:1–8. Pierce K, Courchesne E (2001): Evidence for a cerebellar role in reduced exploration and stereotyped behavior in autism. Biol Psychiatry 49:655–664. Reply We share with Dr. Marazziti and colleagues interest in their intriguing hypothesis regarding a possible link between serotonin and cerebellar pathology in autism. Although cerebellar pathol- ogy is virtually ubiquitous in autism and underlies aspects of neurobehavioral deficits in the disorder, it is only one of several sites of pathology in this disorder. Our recent magnetic resonance imaging investigations of autism reveal striking anatomic growth defects in cerebral and limbic as well as cerebellar structures, and growth defects in each region are present by 2 years of age. A major question is: what molecular mechanisms underlie these early neural growth abnormalities? We agree that serotonin, which influences brain development, could play a role. Karen Pierce Eric Courchesne University of California, San Diego Department of Neurosciences 8110 La Jolla Shores Drive La Jolla, CA 92037 PII S0006-3223(02)01407-5 © 2002 Society of Biological Psychiatry 0006-3223/02/$22.00
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Transcript of A further support to the hypothesis of a link between serotonin, autism, and the cerebellum: Reply
CORRESPONDENCE
A Further Support to the Hypothesis of aLink between Serotonin, Autism, and theCerebellum
To the Editor:We read with much interest the paper of Pierce and
Courchesne published recently in this journal where the authorsreported that a group of children with autism show a decreasedexploratory activity correlating significantly with the cerebellarhypoplasia of vermal lobules VI–VII, and mentioned differentanimal studies involving mutant mice or guinea pigs with geneticdefects provoking Purkinje neuron loss (Pierce and Courchesne2001).
We would like to focus the attention on some articles of ourgroup that may be complementary, in which we hypothesized alink between autism, cerebellum, and the serotonin (5-HT)system (Marazziti et al 1999; Pasqualetti et al 1999), on the basisof the available data and the mRNA expression of a specific5-HT receptor subtypes (i.e., the 5A) in human brain by means ofin-situ hybridization. In fact, we observed in the cerebellum ahigh level of 5-HT5A mRNA expression, particularly in thePurkinje cell perikarya, but also in the granule layer and in thedentate nucleus. This pattern of mRNA expression was found inthe cortex of both hemispheres and the vermis (Pasqualetti et al1999). According to us, the wide distribution of 5-HT5A mRNAin the cerebellum makes this receptor a putative candidate,involved in different functions and, perhaps, in cognitive andemotional processes. This hypothesis is in agreement with theobservation that the 5-HT5A mRNA is expressed in the cortexand in limbic structures, such as the hippocampus and theventrolateral region of the amygdala, whereas it is poorlyrepresented in basal ganglia and absent from substantia nigra,areas both involved in motor function control. When the motorcontrol function of the cerebellum is impaired, the resulting andknown effect is ataxia; we would suggest that similarly, whenimpaired cerebellar control of cognitive and emotional functionsoccurs, the result might be a sort of “cognitive” and “emotional”ataxia, as observed in autism, where subjects appear unable tocoordinate these functions properly.
It is noteworthy that, amongst the functions attributed to5-HT5A, there is a role in brain development and that reelermutant rats exhibit abnormalities of cerebellum, cerebral cortex,hippocampus and olfactory bulbs consistent with the pattern of5-HT5A mRNA expression reported by us, as well as abnormal-ities of exploratory behavior (Grailhe et al 1999) in agreementwith the findings reported by Pierce and Courchesne (2001).
Donatella Marazziti
University of PisaDipartimento di Psichiatria, Neurobiologia, Farmacologia e
BiotecnologieVia Roma, 6756100 Pisa, Italy
PII S0006-3223(02)01406-3
ReferencesGrailhe R, Waeber C, Dulawa SC, Hornung JP, Zhuang X,
Brunner D, et al (1999): Increased exploratory activity andaltered response to LSD in mice lacking 5-HT5A receptor.Neuron 22:5981–5991.
Marazziti D, Nardi I, Cassano GB (1999): Autism, serotonin andcerebellum: Might there be a connection? CNS Spectrums3:80–82.
Pasqualetti M, Ori M, Nardi I, Cassano GB, Castagna A,Marazziti D (1999): Distribution of serotonin 5A receptors inhuman brain. Mol Brain Res 56:1–8.
Pierce K, Courchesne E (2001): Evidence for a cerebellar role inreduced exploration and stereotyped behavior in autism. BiolPsychiatry 49:655–664.
Reply
We share with Dr. Marazziti and colleagues interest in theirintriguing hypothesis regarding a possible link between serotoninand cerebellar pathology in autism. Although cerebellar pathol-ogy is virtually ubiquitous in autism and underlies aspects ofneurobehavioral deficits in the disorder, it is only one of severalsites of pathology in this disorder. Our recent magnetic resonanceimaging investigations of autism reveal striking anatomic growthdefects in cerebral and limbic as well as cerebellar structures, andgrowth defects in each region are present by 2 years of age. Amajor question is: what molecular mechanisms underlie theseearly neural growth abnormalities? We agree that serotonin,which influences brain development, could play a role.
Karen PierceEric Courchesne
University of California, San DiegoDepartment of Neurosciences8110 La Jolla Shores DriveLa Jolla, CA 92037
PII S0006-3223(02)01407-5
© 2002 Society of Biological Psychiatry 0006-3223/02/$22.00
