Synaptic signatures: Understanding thalamocortical circuit specification and disease vulnerability

Sensory processing is frequently altered in disorders like autism, schizophrenia and bipolar disorder.

Neuronal circuits from the thalamus to the primary somatosensory cortex (S1) play a critical role in sensory processing. Dysconnectivity of such circuits is implicated in disorders associated with sensory processing impairments.

The posteromedial thalamic nucleus (POm) connects to intratelencephalic (IT) layer 5 (L5) pyramidal neurons (PNs) of S1, regulating somatosensory processing. The mechanisms regulating connectivity and function of the POm>IT L5 PN circuit remain unknown. Cell surface proteins (CSPs) drive circuit formation and specification.

I hypothesize that a unique combination of CSPs orchestrate the structural and functional connectivity of this circuit, and can explain vulnerability to certain disorders.

To understand the molecular mechanisms involved in POm>IT L5 PN connectivity in mice, I will first isolate POm>IT L5 PN synapses and characterize their molecular signature with mass spectrometry.

Next, I will use these data and information from public databases on the genetics of neurodevelopmental disorders, to select 5 postsynaptic CSPs to further study.

Using genome engineering, I will next knock-out the selected CSPs, one at a time, and analyze the impact on the structure and function of the circuit.

Last, to deepen our mechanistic understanding of these proteins and gain insight to the downstream pathways, I will map changes in the molecular composition of these synapses.

This project will allow us to study for the first time the molecular correlates of the functional specificity of this circuit and provide insight in the pathomechanisms of associated disorders.

The experience of the de Wit lab in studying mechanisms of synapse function, the cutting-edge technologies provided by the host institute and my scientific background will enable me to push the boundaries of existing methods and achieve the highest possible quality in this project.