The developmental loss of cerebellar Purkinje cells that occurs in autism spectrum disorders has been associated with a heterogeneous pattern of cognitive deficits that cannot be explained by a unitary cognitive impairment. It is very unlikely that the simple loss of cerebellar Purkinje cells can directly account for these myriad cognitive deficits. Rather, it is likely that autism is, at its essence, a disconnection syndrome that results, at least in part, from a disruption of cerebellar modulation of the prefrontal cortex (PFC). We have exciting new data suggesting that the cerebellum modulates PFC dopamine levels. Here we propose to investigate the disconnection hypothesis that cerebellar pathology results in dopaminergic abnormalities in the prefrontal cortex (PFC) and underlies some of the core neuropsychiatric symptomatology of autism.
In Aim 1 we will determine the pathway(s) whereby the cerebellum modulates dopamine release in the PFC and glutamate release in subnuclei comprising the cerebellum to PFC pathways and the neurochemical, electrophysiological, anatomical, and behavioral consequences of a disconnection between these two structures.
Aim 1 will compare wildtype (control) and Lurcher mice that loose all Purkinje cells, to determine the consequences of complete loss of Purkinje cells on cerebellar-PFC communication.
Aim 2 will investigate the behavioral and physiological consequences of partial loss of Purkinje cells - as typically found in autistic brains. Using Lurcher-wildtype chimeras with varying developmental loss in Purkinje cell numbers we will determine how neurochemical, electrophysiological, anatomical and behavioral indicators of PFC function depend on Purkinje cell number. Given the well documented reductions in cerebellar neuron number that are found in autism spectrum disorders, the neurochemical, electrophysiological, anatomical and behavioral analyses of chimeric mice presents a unique opportunity to model both the developmental and cerebellar aspects of these syndromes.

Public Health Relevance

Cerebellar and frontal cortical pathologies have been commonly reported in autism and other developmental disorders. The relationship between these two abnormalities is unknown. This proposal presents a framework for understanding how these seemingly disparate pathologies are related, and provides a unique opportunity for discovery of the neurochemical, electrophysiological and anatomical mechanisms whereby the cerebellum may modulate frontal cortical function, with particular focus on dopamine and Purkinje cell numbers. As the details of the functional interactions and adaptations within this neural circuitry become known, these neural substrates and associated receptor mechanisms should become new candidates for treatment of the cognitive deficits related to autism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS063009-05
Application #
8418762
Study Section
Special Emphasis Panel (ZRG1-BDCN-N (02))
Program Officer
Mamounas, Laura
Project Start
2009-03-01
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2013
Total Cost
$286,989
Indirect Cost
$35,175
Name
University of Memphis
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
055688857
City
Memphis
State
TN
Country
United States
Zip Code
38152
Ito, J; Roy, S; Liu, Y et al. (2014) Whisker barrel cortex delta oscillations and gamma power in the awake mouse are linked to respiration. Nat Commun 5:3572
McKimm, Eric; Corkill, Beau; Goldowitz, Dan et al. (2014) Glutamate dysfunction associated with developmental cerebellar damage: relevance to autism spectrum disorders. Cerebellum 13:346-53
Dickson, Price E; Calton, Michele A; Mittleman, Guy (2014) Performance of C57BL/6J and DBA/2J mice on a touchscreen-based attentional set-shifting task. Behav Brain Res 261:158-70
Rogers, Tiffany D; Dickson, Price E; McKimm, Eric et al. (2013) Reorganization of circuits underlying cerebellar modulation of prefrontal cortical dopamine in mouse models of autism spectrum disorder. Cerebellum 12:547-56
Heck, Detlef H; De Zeeuw, Chris I; Jaeger, Dieter et al. (2013) The neuronal code(s) of the cerebellum. J Neurosci 33:17603-9
Dickson, Price E; Corkill, Beau; McKimm, Eric et al. (2013) Effects of stimulus salience on touchscreen serial reversal learning in a mouse model of fragile X syndrome. Behav Brain Res 252:126-35
Roy, Snigdha; Zhao, Yu; Allensworth, Melody et al. (2011) Comprehensive motor testing in Fmr1-KO mice exposes temporal defects in oromotor coordination. Behav Neurosci 125:962-9
Rogers, Tiffany D; Dickson, Price E; Heck, Detlef H et al. (2011) Connecting the dots of the cerebro-cerebellar role in cognitive function: neuronal pathways for cerebellar modulation of dopamine release in the prefrontal cortex. Synapse 65:1204-12
Dickson, Price E; Rogers, Tiffany D; Del Mar, Nobel et al. (2010) Behavioral flexibility in a mouse model of developmental cerebellar Purkinje cell loss. Neurobiol Learn Mem 94:220-8
Martin, Loren A; Goldowitz, Dan; Mittleman, Guy (2010) Repetitive behavior and increased activity in mice with Purkinje cell loss: a model for understanding the role of cerebellar pathology in autism. Eur J Neurosci 31:544-55