Role of GABA signaling in circuit formation of the developing cortex
The mammalian brain is one of the most organized and complex structures in biological systems. The human brain contains about 100 billion neurons that form trillions of synapses. These interconnected elements give us the ability to receive sensory inputs, process and store information, and generate outputs while allowing us to constantly learn and adapt to our environment. Even more fascinating is the fact that this intricate three-dimensional processing machine develops from a single sheet of cells. Understanding how the brain is developed, therefore, is a crucial step to comprehending how the brain functions as a whole.
At the base of the neuronal network is the circuit, containing neurons that form excitatory and inhibitory connections with one another. The development of a balance between these excitatory and inhibitory synapses is a critical process in the generation and maturation of functional circuits. In the immature brain, neuronal activity can play an important role in shaping connections. One neurotransmitter in particular has been implicated in a variety of developmental functions in the nervous system. GABA (γ-aminobutyric acid) is one of the earliest neurotransmitters present in the brain. Unlike in the adult, where this transmitter acts synaptically to inhibit neurons, during development, GABA can depolarize progenitor cells and their progeny due to their high intracellular chloride concentration generated by the Na+-K+-2Cl - cotransporter NKCC1. In addition, the newborn pyramidal neurons in the cortex receive GABAergic inputs before forming glutamatergic connections with each. This early form of GABA signaling may provide the main excitatory drive for the immature cortical network and play a central role in regulating cortical development.
In my dissertation, I hypothesize that this early GABA-induced excitation is critical for the formation of synapses in the neocortex. Using NKCC1 RNAi knockdown in vivo, I show that GABA-induced depolarization is necessary for proper excitatory synapse formation and dendritic development of newborn cortical neurons. Interestingly, expression of a voltage-independent NMDA receptor rescues the failure of NKCC1 knockdown neurons to develop excitatory AMPA transmission, indicating that GABA depolarization cooperates with NMDA receptor activation to regulate excitatory synapse formation. In addition, by blocking NKCC1 pharmacologically with bumetanide during cortical development, I find a critical period for the development of AMPA synapses. Disruption of GABA signaling during this window results in permanent decreases in excitatory synaptic transmission and schizophrenia-like behaviors in adult animals. My study identifies an essential role for GABA-mediated depolarization in regulating the balance between cortical excitation and inhibition during a critical period in cortical development.