Molecular Mechanisms of GABAergic Synaptogenesis
As the major inhibitory neurotransmitter system in the adult central nervous system, GABAergic synapses play a central role in gating the firing of excitatory principal neurons. GABAergic neurons also synapse onto other GABAergic neurons, forming interneuron networks that coordinate ensembles of principal neurons into gamma-frequency oscillatory rhythms thought to contribute to attention and perception, spike-timing based synaptic plasticity, and some forms of memory. Establishing balance between excitatory and inhibitory synaptic transmission is crucial for proper neuronal function and behavior, as dysfunction of GABAergic transmission can lead to epilepsy, and altered excitatory to inhibitory synaptic ratios have been associated with the complex behavioral abnormalities observed in autism and other human neurodevelopmental disorders.

Although recent studies have led to the identification of several key regulators of glutamatergic synaptic assembly in the CNS, the molecular mechanisms of GABAergic synapse formation have been somewhat more elusive, perhaps because of the extensive diversity of molecularly distinct interneuron subclasses that form GABAergic synapses. One intriguing insight comes from the observation that both neuronal activity and Brain-Derived Neurotrophic Factor (BDNF) can drive the formation of new GABAergic synapses in vitro and in vivo, suggesting that these factors tap into programs of gene expression and protein targeting that are crucial for synaptogenesis. We are working to identify these factors by using RNA interference in cultured neurons as well as examining BDNF-induced gene expression programs in identified GFP-expressing GABAergic interneurons to characterize the cellular components that are required for BDNF- and activity-inducible GABAergic synapse formation.

We use transfection of low density neuronal cultures to study how gene manipulation in single cells affects the process of synapse formation.
The image above shows a GFP-transfected neuron (green) grown in culture on a bed of underlying glial cells (labeled for GFAP in blue). Synapses are labeled for synapsin I (red).