Glutamate Dysfunction Associated with Developmental Cerebellar Damage: Relevance to Autism Spectrum Disorders
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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.
KeywordsAutism Cerebellum Dopamine Glutamate Fmr1 mice
This project was made possible by NINDS grant 1R01NS063009.
Conflict of Interest
There are no conflicts of interest.
- 1.American Psychiatric Association. Diagnostic and statistical manual of mental disorders-IV-TR. 4th ed. Washington: American Psychiatric Association; 2000.Google Scholar
- 2.Ozonoff S, South M, Provencal S. Executive functions in autism: theory and practice. In: Pérez JM, GonzálezPM MC, Comí MC, et al., editors. New developments in autism: the future is today. Philadelphia: Asociación de Padres de Personas con Autismo; 2007. p. 185–213.Google Scholar
- 3.Centers for Disease Control and Prevention. Prevalence of autism spectrum disorders— Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2002. MMWR 56(No. SS-1), 12–28, 2007.Google Scholar
- 10.Limperopoulos C, Chilingaryan G, Sullivan N, Guizard N, Robertson RL, du Plessis AJ. Injury to the premature cerebellum: outcome is related to remote cortical development. Cereb Cortex. 2012, Nov 11.Google Scholar
- 19.Goldowitz D, Moran H, Wetts R. Mouse chimeras in the study of genetic and structural determinants of behavior. In: Goldowitz D, Wahlsten D, Wimer RE, editors. Techniques for the genetic analysis of brain and behavior: focus on the mouse. Amsterdam: Elsevier; 1992. p. 271–90.Google Scholar
- 22.Chudasama Y, Passetti F, Rhodes SE, Lopian D, Desai A, Robbins TW. Dissociable aspects of performance on the 5-choice serial reaction time task following lesions of the dorsal anterior cingulate, infralimbic and orbitofrontal cortex in the rat: differential effects on selectivity, impulsivity and compulsivity. Behav Brain Res. 2003;146:105–19.PubMedCrossRefGoogle Scholar
- 36.Agnesi F, Tye SJ, Bledsoe JM, Griessenauer CJ, Kimble CJ, Sieck GC, et al. Wireless instantaneous neurotransmitter concentration system-based amperometric detection of dopamine, adenosine, and glutamate for intraoperative neurochemical monitoring. J Neurosurg. 2009;111:701–11.PubMedCentralPubMedCrossRefGoogle Scholar
- 37.Paxinos G, Franklin KBJ. The mouse brain in stereotaxic coordinates 2nd ed. San Diego: Academic; 2001.Google Scholar