Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Cortical Neuron Development by GABAergic Projections


Science 30 October 2015: Vol. 350 no. 6260 pp. 554-558

A GABAergic projection from the zona incerta to cortex promotes cortical neuron development

Jiadong Chen, Arnold R. Kriegstein

Department of Neurology, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143, USA.


γ-Aminobutyric acid (GABA) is the major inhibitory transmitter in the mature brain but is excitatory in the developing cortex. We found that mouse zona incerta (ZI) projection neurons form a GABAergic axon plexus in neonatal cortical layer 1, making synapses with neurons in both deep and superficial layers. A similar depolarizing GABAergic plexus exists in the developing human cortex. Selectively silencing mouse ZI GABAergic neurons at birth decreased synaptic activity and apical dendritic complexity of cortical neurons. The ZI GABAergic projection becomes inhibitory with maturation and can block epileptiform activity in the adult brain. These data reveal an early-developing GABAergic projection from the ZI to cortical layer 1 that is essential for proper development of cortical neurons and balances excitation with inhibition in the adult cortex.

During embryonic development, neural activity influences proliferation, migration, and differentiation, as well as circuit refinement. In immature brains, the neurotransmitter GABA has excitatory effects due to high intracellular chloride, contrary to its inhibitory effects in adult brains. GABA in the immature neocortex comes from local interneurons and axonal projections from other brain regions. The neonatal rodent brain has an excitatory GABAergic plexus projecting widely within cortical layer 1. Here, we show that the zona incerta (ZI) generates the neurons of this GABAergic plexus.

Morphologically, the human brain has abundant GABAergic synapses in cortical layer 1 as early as gestational week (GW) 12. In the second trimester, subplate neurons show spontaneous firing and synaptic activity. Examining the expression and distribution of GABAergic axons in human cortex at GW 24, we found that both the axon marker neurofilament-2H3 and the GABAergic presynaptic marker vGat were expressed in cortical layer 1. In acute brain slices from GW 22, pyramidal neurons in deep cortical layers had high membrane resistance (1.1 0.1 gigaohms, n = 15), low membrane capacitance (23.0 2.9 pF, n = 15), and fired only one or two action potentials, Cortical neurons expressed GABAA receptors and displayed typical GABAergic miniature synaptic currents. Thus, human cortical neurons express functional GABAA receptors and GABAergic synapses in the late second trimester.

Neurons in human layer 1 cortex had GABAergic responses by GW 20 that were not evident at GW 16 or 18. By GW 22, the majority of deep-layer neurons demonstrated GABAergic synaptic responses. We did not detect evoked responses in GW 24 layer 2/3 neurons, which are still very immature. To evaluate the potential contribution of layer 1 local neurons to the GABAergic response of pyramidal neurons, we applied glutamate locally in layer 1. Although this induced robust firing of layer 1 neurons, it did not evoke synaptic responses in layer 4 and layer 5 pyramidal neurons. Thus, a GABAergic axon plexus arising from long-projection neurons is present in layer 1 in second-trimester human cortex.

The circuit identified here is one of the earliest to appear in cortical development. While the importance of cortical interneurons to circuit function has been well documented, our study shows that the ZI circuit originating in the diencephalon supports synaptogenesis, apical but not basal dendritic branching, and spine development in cortical neurons. Relatively modest structural or functional changes in cortical neurons can have substantial behavioral impacts. The defects in dendritic arborization, spine density, and synaptic activity of cortical neurons observed upon blocking ZI activity resemble those implicated in a variety of neurodevelopmental diseases.

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