Our laboratory studies how synapses form between neurons in the cerebral cortex and how excitatory and inhibitory synaptic signals are integrated within cerebral cortical neurons.
The neural circuits that govern perception and behavior are composed of networks of neurons that communicate with one another via synapses. As our brains develop, the roughly 10-20 billion neurons that comprise the human cerebral cortex are presented with the enormous and complex task of forming trillions of synapses. To make matters more complicated, synapses must form specifically between appropriate neuronal partners to establish functional neural circuits. Understanding cortical synaptogenesis and circuit assembly is essential for understanding normal brain function.
Errors in circuit development are
increasingly being linked to development of diseases such as autism, mental retardation, anxiety disorders,
depression, epilepsy, and schizophrenia.
Understanding the causes of these diseases is of tremendous importance since
they affect a huge number of people. For example, autism affects one of every
160-600 children, while anxiety disorders and depression are estimated to
afflict over 20% and nearly 10% of the population, respectively. In order to
determine how circuit development is disrupted in such diseases, it is
necessary to understand the fundamental
molecular and cellular mechanisms of synapse formation.
Synaptogenesis is also important for repair after brain injury, integration of stem cell-derived neurons into neuronal networks, and treatment of disorders like Alzheimer's Disease in which synapse loss occurs prior to diagnosis.
Assembly of presynaptic terminals requires rapid, site-specific recruitment and stabilization of the proteins essential for localized, reliable neurotransmitter release. We have shown previously that synapse formation is restricted to specific sites along axons that are defined even prior to axo-dendritic contact. We are currently studying how presynaptic terminal assembly is coordinated during trafficking and recruitment of synaptic proteins to these predefined sites. We study synapse formation using live confocal imaging of fluorescently-tagged proteins and dyes.
Another project in the lab is to determine the role of glutamate and presynaptic NMDA receptors during early stages of synapse formation. Glutamate is released from neocortical neurons prior to synapse formation, but how this released glutamate contributes to synapse formation is not yet clear. Similarly, many developing neocortical pyramidal neurons express presynaptic NMDA receptors, but their function during synapse development has not been studied.
A third project in the lab is to identify molecules that control synapse assembly. Recent work from several labs has identified genes that control synapse formation in invertebrate model systems. We are testing whether these same molecular mechanisms control synaptogenesis in mammalian cerebral cortical neurons.
During development, specificity of neural circuitry is established by forming the right kind and number of synapses with the right synaptic partners. Each neuron receives both excitatory and inhibitory synaptic inputs, targeted to specific subcellular domains. These excitatory and inhibitory synapses comprise both feed-forward and feed-back circuits. Activation of different groups of these synapses can affect neuronal function differently. However, we are only beginning to understand how different groups of synapses are integrated by a neuron to define its functional properties within its circuits.
project in the lab that is currently underway is to define how excitatory and
inhibitory synapses that come from different sources (e.g. feed-forward with
common inputs vs. feed-forward with uncommon inputs vs. feed-back) are
integrated in a neuron to determine its firing properties. To do this, we are
using a computer-based dynamic clamp system and patch clamp electrophysiology
to simulate different combinations of synaptic inputs.
Understanding how excitatory and inhibitory synapses
are integrated and the extent to which the properties of this integration
depend on the source of the synapse is important for a several reasons. It is
necessary for understanding normal brain function. It is also important for
understanding how altered synapse formation affects functional neuronal
circuitry (e.g. how does having more synapses from different synaptic partners
compare with having more synapses from the same partner?). Finally, it has been
suggested that an imbalance of excitation to inhibition can cause diseases such
as autism spectrum disorders and epilepsy but how an imbalance of excitation
and inhibition affects neuronal function remains unclear.