One area of our research focuses on the establishment and refinement of synaptic circuits during development. We have characterized, using electrophysiological techniques, the refinement of the retinogeniculate synapse during development as initially overabundant inputs are either eliminated or strengthened to establish the mature circuit. We have also made the surprising finding that this thalamic synapse retains the ability to refine and remodel during late development — beginning around postnatal day 20 in mice, there is a critical period during which connections between retinal ganglion cells (RGC) and thalamic relay neurons can re-wire with experience. To identify and characterize the mechanisms that mediate the different phases of remodeling of this synapse, we are taking advantage of genetically altered mice and viral-mediated circuit manipulations to elucidate the roles of specific molecular cues and plasticity mechanisms.
Another area of interest relates to interactions between cortex and thalamus. In the traditional view of neural development, sensory pathways develop sequentially in a feedforward manner. In the visual system, retinal circuits were thought to mature first and direct refinement in the thalamus, where circuits would then stabilize locally before directing refinement in cortex, which was considered the main locus for experience-dependent plasticity. Surprisingly, the critical period of plasticity in thalamus occurs almost simultaneous to that in the cortex, suggesting that interactions between thalamus and cortex contribute to the refinement of sensory circuits. Indeed, our more recent studies demonstrate that feedback from cortex to thalamus critically regulates refinement of the retinogeniculate projection during the window for experience-dependent plasticity. We are interested in understanding the molecular and circuit-dependent mechanisms that mediate this plasticity.
We are also studying how disruption of developmental formation and refinement of synaptic circuits can lead to neurodevelopmental disorders such as autism spectrum disorders, intellectual disabilities, neuropsychiatric disorders and epilepsy. Work from our lab demonstrated that defects in experience-dependent plasticity underlie a subset of neurodevelopmental disorders. In a mouse model for Rett Syndrome, a disorder that exhibits autism-like symptoms, we showed that after initially normal development of the retinogeniculate synapse, a progressive disruption of the circuit occurs during the period of experience-dependent plasticity. In Mecp2 KO mice, synaptic remodeling in response to changes in sensory experience is abnormal, suggesting a defect in the adaptation of synaptic circuits to the sensory environment. A current interest in the lab is whether this process involves abnormal interactions between cortex and thalamus, and whether this process is generalizable to other neurodevelopmental disorders.
In mature visual system, we are interested in understanding how visual information is encoded in the thalamus. In the mouse retina, there are at least 30 different subtypes of retinal ganglion cells that code for various aspects of the receptive field. We are studying how this information is integrated or segregated in the thalamus through a combination of patch clamp recordings in a brain slice preparations of the lateral geniculate nucleus and the thalamic reticular nucleus, as well as in vivo imaging of retinal axons and their postsynaptic targets in awake behaving mice. We are also characterizing the synaptic mechanisms and neuromodulatory projections that regulate the decoding of retinal cell firing patterns in thalamocortical relay neurons.