Reorganization of Circuits Underlying Cerebellar Modulation of Prefrontal Cortical Dopamine in Mouse Models of Autism Spectrum Disorder

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.

Meta-analytic connectivity and behavioral parcellation of the human cerebellum

“…Cerebellar co-activation with regions of the pre-SMA, SMA, and cingulate motor areas indicates involvement with the cognitive control and execution of motor actions (Akkal et al, 2007; Nachev et al, 2008; Amiez and Petrides, 2014), while regions in the anterior cingulate and insular cortices exhibit involvement in error-processing and subsequent behavioral adjustments (e.g., Danielmeier et al, 2011). Furthermore, motor responses are critically associated with dopaminergic function (Durieux et al, 2011; Rogers et al, 2013), as is error-processing (Holroyd et al, 2002). Involvement in these motor and cognitive functions is consistent with theories highlighting a role of the cerebellum in regulating dopaminergic function and serving as a forward controller and toggling cortical circuits between automatic and controlled processes (Dosenbach 2006; Ramnani 2014).…”

Autism and cerebellar dysfunction: Evidence from animal models

“…Lurcher/chimeric mice, which display impaired working memory and inflexibility behaviors, demonstrate abnormalities in distributed neuronal circuitry from cerebellum to medial prefrontal cortex. Fragile X mutant mice demonstrated disrupted cerebellarecortical circuitry that approximates the disruption seen in Lurcher chimeric animals, implicating disruption of these distributed circuits in ASD behaviors [47]. However, a functional contribution of these neuronal circuits to ASD behaviors remains to be determined.…”

“…Mouse models demonstrate similar anatomic deficits with the naturally occurring Lurcher mutant mouse (which possesses a Grid2 mutation) demonstrating significant cerebellar neuronal loss in addition to behavioral ataxia. Lurcher chimeric animals also display working memory deficits and cognitive inflexibility in addition to disrupted circuitry from cerebellar hemispheres to medial prefrontal cortex [47].…”

Targeted pharmacological treatment of autism spectrum disorders: fragile X and Rett syndromes

“…Deficits in the dopamine system have been demonstrated in both fragile X animal models and patients (Roberts et al, 2005; Wang et al, 2008b; Weinshenker and Warren, 2008; Fulks et al, 2010; Paul et al, 2013; Rogers et al, 2013). Electrophysiological studies have found that dopaminergic modulation of synaptic transmission and potentiation are impaired in fragile X mice (Wang et al, 2008b; Paul et al, 2013).…”