A cerebellar abnormality is one of the most prominent characteristics of brain pathology in various neurological disorders, including autism spectrum disorders, Down syndrome, and schizophrenia. Nevertheless, the role of the cerebellum in these disorders, especially in cognitive impairment, had been unclear for decades because the cerebellum has traditionally been thought to regulate sensorimotor behavior. Recently, studies in autism research strongly suggest that cerebellar dysfunction indeed causes social and cognitive impairments, highlighting a fundamental gap between the traditional view of the cerebellum and its actual function. In order to fill the gap, many recent studies aim to understand the connectivity and functional interaction between the cerebellum and neocortex because social and cognitive behaviors are primarily regulated by the prefrontal area of the neocortex. While these studies are undeniably important and expected to provide significant new insight into the role of the cerebellum in non-motor, cognitive behavior in adult animals, a potential role of the cerebellum in brain development has been largely overlooked. Neuronal activity is known to play crucial roles in the formation of synaptic circuits during development. The cerebellum sends dense excitatory projections to the forebrain, and damage to the developing cerebellum often causes autistic symptoms. Therefore, it is highly reasonable to hypothesize that cerebellar dysfunction early in life impairs neuronal activity-dependent phase of forebrain development, which would disturb not only motor but also non-motor functions of the brain. To test this hypothesis, we will first focus on the thalamus. The thalamus is the heart of cerebello-forebrain interaction. It receives direct, excitatory synaptic inputs from the cerebellum and relays cerebellar activity to the motor and non-motor areas of the neocortex. If thalamic circuits are not formed properly, functional interaction between the cerebellum and neocortex is disturbed. Anatomical and functional properties of cerebellothalamic circuits have been characterized in mature animals. However, surprisingly little is known about their maturation process.
In Aim 1 of the proposed research, whole-cell patch-clamp recording and axonal tracing will be combined to determine how morphological and functional properties of cerebellothalamic synapses, as well as intrinsic excitability of thalamic neurons, develop in the normal brain.
In Aim 2, transgenic mouse lines that have cerebellar-specific cell/gene mutations will be used to determine how cerebellar dysfunction early in life affects the formation of cerebellothalamic circuits. This contribution is significant because it is expected to establish a novel role of the cerebellum as a regulator of forebrain development and provides a new conceptual framework for understanding how cerebellar abnormalities cause neurological disorders.
The interaction between the cerebellum and forebrain is a key to understand how cerebellar dysfunction causes neurological disorders with cognitive impairment, such as autism. The proposed research aims to establish a novel concept that cerebellar dysfunction early in life disturbs the formation of thalamic circuits: the hub of cerebello-forebrain interaction. Thus, this project is directly relevant to the part of NIH?s mission that pertains to reducing the burden of neurological diseases through basic research.
