Reorganization of circuits underlying cerebellar modulation of prefrontal cortical dopamine in mouse models of autism spectrum disorder

Tiffany D. Rogers, Price E. Dickson, Eric McKimm, Detlef Heck, Dan Goldowitz, Charles D. Blaha, Guy Mittleman

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Imaging, clinical, and pre-clinical studies have provided ample evidence for a cerebellar involvement in cognitive brain function including cognitive brain disorders, such as autism and schizophrenia. We previously reported that cerebellar activity modulates dopamine release in the mouse medial prefrontal cortex (mPFC) via two distinct pathways: (1) cerebellum to mPFC via dopaminergic projections from the ventral tegmental area (VTA) and (2) cerebellum to mPFC via glutamatergic projections from the mediodorsal and ventrolateral thalamus (ThN md and vl). The present study compared functional adaptations of cerebello-cortical circuitry following developmental cerebellar pathology in a mouse model of developmental loss of Purkinje cells (Lurcher) and a mouse model of fragile X syndrome (Fmr1 KO mice). Fixed potential amperometry was used to measure mPFC dopamine release in response to cerebellar electrical stimulation. Mutant mice of both strains showed an attenuation in cerebellar-evoked mPFC dopamine release compared to respective wildtype mice. This was accompanied by a functional reorganization of the VTA and thalamic pathways mediating cerebellar modulation of mPFC dopamine release. Inactivation of the VTA pathway by intra-VTA lidocaine or kynurenate infusions decreased dopamine release by 50 % in wildtype and 20-30 % in mutant mice of both strains. Intra-ThN vl infusions of either drug decreased dopamine release by 15 % in wildtype and 40 % in mutant mice of both strains, while dopamine release remained relatively unchanged following intra-ThN md drug infusions. These results indicate a shift in strength towards the thalamic vl projection, away from the VTA. Thus, cerebellar neuropathologies associated with autism spectrum disorders may cause a reduction in cerebellar modulation of mPFC dopamine release that is related to a reorganization of the mediating neuronal pathways.

Original languageEnglish (US)
Pages (from-to)547-556
Number of pages10
JournalCerebellum
Volume12
Issue number4
DOIs
StatePublished - Aug 1 2013

Fingerprint

Prefrontal Cortex
Ventral Tegmental Area
Dopamine
Mutant Strains Mice
Cerebellum
Neurologic Mutant Mice
Kynurenic Acid
Ventral Thalamic Nuclei
Fragile X Syndrome
Dopamine Agents
Purkinje Cells
Brain Diseases
Autistic Disorder
Lidocaine
Autism Spectrum Disorder
Cognition
Electric Stimulation
Schizophrenia
Pathology
Brain

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology

Cite this

Reorganization of circuits underlying cerebellar modulation of prefrontal cortical dopamine in mouse models of autism spectrum disorder. / Rogers, Tiffany D.; Dickson, Price E.; McKimm, Eric; Heck, Detlef; Goldowitz, Dan; Blaha, Charles D.; Mittleman, Guy.

In: Cerebellum, Vol. 12, No. 4, 01.08.2013, p. 547-556.

Research output: Contribution to journalArticle

Rogers, Tiffany D. ; Dickson, Price E. ; McKimm, Eric ; Heck, Detlef ; Goldowitz, Dan ; Blaha, Charles D. ; Mittleman, Guy. / Reorganization of circuits underlying cerebellar modulation of prefrontal cortical dopamine in mouse models of autism spectrum disorder. In: Cerebellum. 2013 ; Vol. 12, No. 4. pp. 547-556.
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