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The role of cerebellar circuitry alterations in the pathophysiology of autism spectrum disorders.

Mosconi MW, Wang Z, Schmitt LM, Tsai P, Sweeney JA - Front Neurosci (2015)

Bottom Line: Each of these behaviors has been found to be impaired in ASD, suggesting that multiple distinct circuits of the cerebellum may be involved in the pathogenesis of patients' sensorimotor impairments.Preclinical studies of monogenetic conditions associated with ASD also have identified selective defects of the cerebellum and documented behavioral rescues when the cerebellum is targeted.Based on these findings, we propose that cerebellar circuits may prove to be promising targets for therapeutic development aimed at rescuing sensorimotor and other clinical symptoms of different forms of ASD.

View Article: PubMed Central - PubMed

Affiliation: Clinical Child Psychology Program and Schiefelbusch Institute for Life Span Studies, University of Kansas Lawrence, KS, USA ; Center for Autism and Developmental Disabilities, University of Texas Southwestern Dallas, TX, USA ; Department of Psychiatry, University of Texas Southwestern Dallas, TX, USA ; Department of Pediatrics, University of Texas Southwestern Dallas, TX, USA.

ABSTRACT
The cerebellum has been repeatedly implicated in gene expression, rodent model and post-mortem studies of autism spectrum disorder (ASD). How cellular and molecular anomalies of the cerebellum relate to clinical manifestations of ASD remains unclear. Separate circuits of the cerebellum control different sensorimotor behaviors, such as maintaining balance, walking, making eye movements, reaching, and grasping. Each of these behaviors has been found to be impaired in ASD, suggesting that multiple distinct circuits of the cerebellum may be involved in the pathogenesis of patients' sensorimotor impairments. We will review evidence that the development of these circuits is disrupted in individuals with ASD and that their study may help elucidate the pathophysiology of sensorimotor deficits and core symptoms of the disorder. Preclinical studies of monogenetic conditions associated with ASD also have identified selective defects of the cerebellum and documented behavioral rescues when the cerebellum is targeted. Based on these findings, we propose that cerebellar circuits may prove to be promising targets for therapeutic development aimed at rescuing sensorimotor and other clinical symptoms of different forms of ASD.

No MeSH data available.


Related in: MedlinePlus

The microstructural organization of the cerebellar cortex showing the presence of three layers and the relative position of Purkinje, basket, stellate, and Golgi cells and the main inputs (mossy and climbing fibers) of the cerebellum. There are two main afferents to the cerebellar cortex: climbing fibers, which make direct excitatory contact with the Purkinje cells, and mossy fibers, which terminate in the granular layer and make excitatory synaptic contacts primarily with granule cells, but also with Golgi cells. The ascending axons of the granule cells branch in a T-shaped manner to form the parallel fibers, which, in turn, make excitatory synaptic contacts with Purkinje cells and molecular layer interneurons including stellate and basket cells.
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Figure 1: The microstructural organization of the cerebellar cortex showing the presence of three layers and the relative position of Purkinje, basket, stellate, and Golgi cells and the main inputs (mossy and climbing fibers) of the cerebellum. There are two main afferents to the cerebellar cortex: climbing fibers, which make direct excitatory contact with the Purkinje cells, and mossy fibers, which terminate in the granular layer and make excitatory synaptic contacts primarily with granule cells, but also with Golgi cells. The ascending axons of the granule cells branch in a T-shaped manner to form the parallel fibers, which, in turn, make excitatory synaptic contacts with Purkinje cells and molecular layer interneurons including stellate and basket cells.

Mentions: A unifying framework for the cerebellum appears plausible in the context of its relatively invariant cellular architecture that contrasts the diversity of cellular composition across different neocortical areas. The cerebellar cortex consists of numerous “microcomplexes” that are structured similarly across lobules and different subregions (Ito, 2008) (Figure 1). These microcomplexes are comprised of mossy fiber inputs, primarily originating from pontine nuclei but also from vestibular nuclei, the spinal cord, and reticular formation. Mossy fibers innervate Purkinje cells of the cerebellar cortex via granular cells and parallel fibers as well as feedback collaterals from deep cerebellar nuclei. Excitatory mossy fiber inputs provide information from neocortical regions as well as the spinal cord (Vogel et al., 1996; Ramnani, 2006; Geborek et al., 2014). Climbing fibers originating in the inferior olive communicate instructional or “teaching” signals directly to Purkinje cells and initiate a process of long-term depression (LTD) that selectively prunes parallel fiber-Purkinje cell synapses and modifies the strength of inhibitory output from Purkinje cells to deep nuclei (Nguyen-Vu et al., 2013). This process is the basis of cerebellar learning and it allows the cerebellum to consolidate and then modify internal models of action that are used to predictively control motor behavior (Wolpert et al., 1998).


The role of cerebellar circuitry alterations in the pathophysiology of autism spectrum disorders.

Mosconi MW, Wang Z, Schmitt LM, Tsai P, Sweeney JA - Front Neurosci (2015)

The microstructural organization of the cerebellar cortex showing the presence of three layers and the relative position of Purkinje, basket, stellate, and Golgi cells and the main inputs (mossy and climbing fibers) of the cerebellum. There are two main afferents to the cerebellar cortex: climbing fibers, which make direct excitatory contact with the Purkinje cells, and mossy fibers, which terminate in the granular layer and make excitatory synaptic contacts primarily with granule cells, but also with Golgi cells. The ascending axons of the granule cells branch in a T-shaped manner to form the parallel fibers, which, in turn, make excitatory synaptic contacts with Purkinje cells and molecular layer interneurons including stellate and basket cells.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4555040&req=5

Figure 1: The microstructural organization of the cerebellar cortex showing the presence of three layers and the relative position of Purkinje, basket, stellate, and Golgi cells and the main inputs (mossy and climbing fibers) of the cerebellum. There are two main afferents to the cerebellar cortex: climbing fibers, which make direct excitatory contact with the Purkinje cells, and mossy fibers, which terminate in the granular layer and make excitatory synaptic contacts primarily with granule cells, but also with Golgi cells. The ascending axons of the granule cells branch in a T-shaped manner to form the parallel fibers, which, in turn, make excitatory synaptic contacts with Purkinje cells and molecular layer interneurons including stellate and basket cells.
Mentions: A unifying framework for the cerebellum appears plausible in the context of its relatively invariant cellular architecture that contrasts the diversity of cellular composition across different neocortical areas. The cerebellar cortex consists of numerous “microcomplexes” that are structured similarly across lobules and different subregions (Ito, 2008) (Figure 1). These microcomplexes are comprised of mossy fiber inputs, primarily originating from pontine nuclei but also from vestibular nuclei, the spinal cord, and reticular formation. Mossy fibers innervate Purkinje cells of the cerebellar cortex via granular cells and parallel fibers as well as feedback collaterals from deep cerebellar nuclei. Excitatory mossy fiber inputs provide information from neocortical regions as well as the spinal cord (Vogel et al., 1996; Ramnani, 2006; Geborek et al., 2014). Climbing fibers originating in the inferior olive communicate instructional or “teaching” signals directly to Purkinje cells and initiate a process of long-term depression (LTD) that selectively prunes parallel fiber-Purkinje cell synapses and modifies the strength of inhibitory output from Purkinje cells to deep nuclei (Nguyen-Vu et al., 2013). This process is the basis of cerebellar learning and it allows the cerebellum to consolidate and then modify internal models of action that are used to predictively control motor behavior (Wolpert et al., 1998).

Bottom Line: Each of these behaviors has been found to be impaired in ASD, suggesting that multiple distinct circuits of the cerebellum may be involved in the pathogenesis of patients' sensorimotor impairments.Preclinical studies of monogenetic conditions associated with ASD also have identified selective defects of the cerebellum and documented behavioral rescues when the cerebellum is targeted.Based on these findings, we propose that cerebellar circuits may prove to be promising targets for therapeutic development aimed at rescuing sensorimotor and other clinical symptoms of different forms of ASD.

View Article: PubMed Central - PubMed

Affiliation: Clinical Child Psychology Program and Schiefelbusch Institute for Life Span Studies, University of Kansas Lawrence, KS, USA ; Center for Autism and Developmental Disabilities, University of Texas Southwestern Dallas, TX, USA ; Department of Psychiatry, University of Texas Southwestern Dallas, TX, USA ; Department of Pediatrics, University of Texas Southwestern Dallas, TX, USA.

ABSTRACT
The cerebellum has been repeatedly implicated in gene expression, rodent model and post-mortem studies of autism spectrum disorder (ASD). How cellular and molecular anomalies of the cerebellum relate to clinical manifestations of ASD remains unclear. Separate circuits of the cerebellum control different sensorimotor behaviors, such as maintaining balance, walking, making eye movements, reaching, and grasping. Each of these behaviors has been found to be impaired in ASD, suggesting that multiple distinct circuits of the cerebellum may be involved in the pathogenesis of patients' sensorimotor impairments. We will review evidence that the development of these circuits is disrupted in individuals with ASD and that their study may help elucidate the pathophysiology of sensorimotor deficits and core symptoms of the disorder. Preclinical studies of monogenetic conditions associated with ASD also have identified selective defects of the cerebellum and documented behavioral rescues when the cerebellum is targeted. Based on these findings, we propose that cerebellar circuits may prove to be promising targets for therapeutic development aimed at rescuing sensorimotor and other clinical symptoms of different forms of ASD.

No MeSH data available.


Related in: MedlinePlus