Our Current Focus
TUBEROUS SCLEROSIS 1 (TSC1) REGULATION OF MEMBRANE EXCITABILITY
Autism spectrum disorder (ASD) is a complex and heterogeneous disorder with a clear genetic etiology. Multiple lines of evidence indicate that dysfunction in cerebellar circuits contribute to ASD pathogenesis. However, the molecular and cellular mechanisms underlying this dysfunction are not understood. Tuberous sclerosis complex (Tsc) is a developmental disorder caused by loss of function mutations in Tsc1 or Tsc2 that is known to affect cerebellar function directly. TSC mutations are also one of the most prevalent monogenetic (mutation in a single gene) causes of autism. Interestingly, mice that have Tsc1 selectively deleted from Purkinje neurons in the cerebellum display several autistic-like behaviors. These Purkinje neurons (that lack Tsc1) were found to fire action potentials at slower rates than wild type (regular) mice. This tells us that messing up the firing of Purkinje neurons alone can lead to autsitic behaviors. Which is huge! But there is a lot we still don't understand. We have no idea why the loss of Tsc1 causes Purkinje neurons to fire more slowly. In this project, we will use electrophysiology, molecular genetic and behavioral techniques to determine why the loss of Tsc1 slows the firing of Purkinje neurons and determine how this slowed firing affects the cerebellar functions.
ARE THE NEURONAL CIRCUITS THROUGHOUT THE CEREBELLUM BUILT THE SAME?
There are discrete neuronal circuits in the cerebellum that underlie different types of behaviors. Interconnected inferior olive (IO) neurons, Purkinje neurons, and deep cerebellar nuclei (DCN) neurons form closed-loop olivo-cerebellar circuits (see the image below), and these closed-loop circuits comprise the operational unit of the cerebellum. Cerebellar circuits are arranged longitudinally (in the sagittal plane) across the 10 lobules of the cerebellum and are anatomically organized into discrete ‘modules’. In each module, several bands of Purkinje neurons receive common excitatory input from a specific section of the IO and project inhibitory axons to a discrete set of DCN neurons. The electrical outputs of these cerebellar circuits regulate the timing and coordination of several types of behavior, and while studies continue to define and link precise cerebellar circuits with behavior, there is consensus that the circuits that converge onto the Purkinje neurons in the spinocerebellum (in cerebellar lobules I-V and VIII) have primarily functions related to movement, while circuits in the neocerebellum (in lobules VI and VII) contribute to cognition and emotion. Additionally, circuits in the vestibulocerebellum (lobule X) carry out vestibular functions. Cerebellar Purkinje neurons have intrinsic electrical properties that drive repetitive firing that is crucial for all of these cerebellum-related behaviors. Interestingly, the rates and patterns of Purkinje neuron firing are heterogeneous across the different olivo-cerebellar circuits and lobules in the cerebellum. Using electrophysiology, molecular and behavior studies, we will determine what makes the Purkinje neurons unique and different across these cerebellar areas.