Gaba Regulates Synaptic Integration of Newly Generated Neurons in the Adult Brain

by Zamazimba Madi

Adult neurogenesis is the process in which neurons are generated from neural stem cells in the adult, it is a form of structural neuroplasticity and emphasizes regenerative ability of the adult mammalian brain​. It is known that neuronal activity regulates adult neurogenesis and, new neurons contribute to specific brain functions​. It is unknown how the integration of these new neurons into the existing functional neuronal circuits is regulated​. Expect to see that newborn granule cells are tonically activated by ambient GABA (γ-aminobutyric acid, an inhibitory neurotransmitter in the central nervous system) before sequential innervation by GABA- and glutamate-mediated synaptic inputs​. GABA initially depolarizes newborn neurons owing to their high cytoplasmic chloride content​. In vivo, GABA-induced depolarization converted into hyperpolarization in newborn neurons results in marked defects in synapse formation and dendritic development​. The purpose of this study was to establish the role of GABA in the synaptic integration and proposes a mechanism for the regulation of adult neurogenesis​.

DEVELOPMENT OF NEWBORN CELLS IN THE ADULT MICE

Thus, new-born cells are tonically activated by ambient GABA before any detectable phasic or synaptic activation, and we can conclude that new-born cells in the adult brain, as in neonates, first receive tonic GABA activation, then GABA-mediated synaptic inputs and finally glutamate-mediated synaptic inputs.

NATURE OF GABA-INDUCED ACTIVATION IN NEWBORN CELLS IN THE ADULT BRAIN​

GABA initially depolarizes new-born cells in the adult brain.  Tonic GABA activation led to hyperpolarization of NKCC1- shRNA [sodium (Na), potassium (K), chloride (Cl) co-transporter 1- short/small hairpin RNA (an artificial RNA molecule with a tight hairpin turn that can be used to silence target gene expression via RNA interference its expression in these cells is usually achieved through the delivery of plasmids or viral or bacterial vectors. See image (Sliva & Schnierle, 2010)) expressing cells in contrast to depolarization on the control new-born cells. GABA depolarizes new-born cells during initial development due to their high chloride ion concentration from the expression of NKCC1. Therefore, tonic GABA activation not only depolarizes new-born cells but is also the bulk of GABA-induced activation during initial integration when phasic or synaptic GABA activation is weaker than tonic activation or does not exist.

SYNAPTIC INTEGRATION OF NEWBORN CELLS IN THE ADULT BRAIN

There are defects in the formation of GABA-mediated synapses by NKCC1-shRNA-expressing cells. Results show that postsynaptic currents and spontaneous synaptic currents were detected in NKCC1-shRNA-expressing cells halfway through the experiment, and the percentage of cells recorded with postsynaptic currents was largely reduced two weeks later.  Therefore, there were no general defects in receptor expression at the synapses.

DENDRITIC DEVELOPMENT OF NEWBORN CELLS IN THE ADULT BRAIN

NKCC1-shRNA expressing cells had marked defects in dendritic arborization i.e., total dendritic length, branch number and complexity were reduced.  Therefore, GABA-induced depolarization regulates the dendritic development of new-born neurons in the adult brain.

In conclusion, the integration of newborn neurons into existing functional circuitry involves tonic GABA activation to GABA-mediated synaptic innervation, then glutamate-mediated synaptic innervation​. GABA initially depolarizes newborn neurons, as it would neonatal neurons because of their high cytoplasmic chloride ion content from NKCC1 expression​. Converting GABA-induced excitation into inhibition leads to marked defects in the development of GABA- and glutamate-mediated synapses and dendritic development in newborn neurons​. Tonic GABA activation depolarizes newborn neurons and phasic activation non-existent or weaker​. A possible mechanism was proposed for activity-dependent regulation of adult neurogenesis i.e., through new neurons that sense neuronal network activities through local ambient GABA levels before receiving synaptic innervations​. The results from this experiment can be applied stem cell cell-replacement therapy for neurodegenerative diseases​.

REFERENCES

Ge, S., Goh, E.L., Sailor, K.A., Kitabatake, Y., Ming, G.L. and Song, H., 2006. GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature439(7076), pp.589-593.

Sliva, K. and Schnierle, B.S., 2010. Selective gene silencing by viral delivery of short hairpin RNA. Virology journal7(1), pp.1-11.

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