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Glutamate Dysfunction Associated with Developmental Cerebellar Damage: Relevance to Autism Spectrum Disorders

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Abstract

Neural abnormalities commonly associated with autism spectrum disorders include prefrontal cortex (PFC) dysfunction and cerebellar pathology in the form of Purkinje cell loss and cerebellar hypoplasia. It has been reported that loss of cerebellar Purkinje cells results in aberrant dopamine neurotransmission in the PFC which occurs via dysregulation of multisynaptic efferents from the cerebellum to the PFC. Using a mouse model, we investigated the possibility that developmental cerebellar Purkinje cell loss could disrupt glutamatergic cerebellar projections to the PFC that ultimately modulate DA release. We measured glutamate release evoked by local electrical stimulation using fixed-potential amperometry in combination with glutamate selective enzyme-based recording probes in urethane-anesthetized Lurcher mutant and wildtype mice. Target sites included the mediodorsal and ventrolateral thalamic nuclei, reticulotegmental nuclei, pedunculopontine nuclei, and ventral tegmental area. With the exception of the ventral tegmental area, the results indicated that in comparison to wildtype mice, evoked glutamate release was reduced in Lurcher mutants by between 9 and 72 % at all stimulated sites. These results are consistent with the notion that developmental loss of cerebellar Purkinje cells drives reductions in evoked glutamate release in cerebellar efferent pathways that ultimately influence PFC dopamine release. Possible mechanisms whereby reductions in glutamate release could occur are discussed.

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Acknowledgments

This project was made possible by NINDS grant 1R01NS063009.

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There are no conflicts of interest.

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Authors and Affiliations

  1. Department of Psychology, The University of Memphis, 400 Innovation Drive, Memphis, TN, 38152, USA

    Eric McKimm, Beau Corkill, Charles D. Blaha & Guy Mittleman

  2. Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada

    Dan Goldowitz

  3. Microbiology, Immunology and Biochemistry, The University of Tennessee Health Science Center, 858 Madison Ave., Memphis, TN, 38163, USA

    Lorraine M. Albritton

  4. Bioinformatics Program & Center for Translational Informatics, Department of Biology, The University of Memphis, 3774 Walker Ave, Memphis, TN, 38152, USA

    Ramin Homayouni

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  1. Eric McKimm
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Correspondence to Guy Mittleman.

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McKimm, E., Corkill, B., Goldowitz, D. et al. Glutamate Dysfunction Associated with Developmental Cerebellar Damage: Relevance to Autism Spectrum Disorders. Cerebellum 13, 346–353 (2014). https://doi.org/10.1007/s12311-013-0541-4

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