title: Glutamate dysfunction associated with developmental cerebellar damage: relevance to autism spectrum disorders.
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.
authors.affiliation: Department of Psychology, The University of Memphis, 400 Innovation Drive, Memphis, TN, 38152, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: McKimm
authors.forename: Beau
authors.initials: B
authors.lastname: Corkill
authors.forename: Dan
authors.initials: D
authors.lastname: Goldowitz
authors.forename: Lorraine M
authors.initials: LM
authors.lastname: Albritton
authors.forename: Ramin
authors.initials: R
authors.lastname: Homayouni
authors.forename: Charles D
authors.initials: CD
authors.lastname: Blaha
authors.forename: Guy
authors.initials: G
authors.lastname: Mittleman
mesh_terms: D000818:Animals; D001927:Brain Diseases / Q000209:etiology / Q000378:metabolism*; D002659:Child Development Disorders, Pervasive / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D051379:Mice; D017397:Prefrontal Cortex / Q000503:physiopathology*; D011689:Purkinje Cells / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D018698:Glutamic Acid; D004298:Dopamine