Insufficient developmental excitatory neuronal activity fails to foster establishment of normal levels of inhibitory neuronal activity. Issue 55 (26th September 2016)

• Record Type: Journal Article
• Authors: Therrien, Mikaela; Vohnoutka, Rishel; Boumil, Edward; Guaraldi, Mary; Lee, Sangmook; Shea, Thomas B.
• Is Part Of: International journal of developmental neuroscience. Issue 55(2016:Dec.)
• Page Start: 66
• Page End: 71
• Publication Date: 2016-09-26
• Subjects: Neurons -- Inhibitory neurons -- Nervous system development -- Multi‐electrode array -- Neuronal culture; Developmental neurobiology -- Periodicals; Neurology -- Periodicals; Neurologie du développement -- Périodiques; Developmental neurobiology; Periodicals; 612.8
• DOI: 10.1016/j.ijdevneu.2016.09.009
• Languages: English
• ISSNs: 0736-5748

Abstract

Abstract: The nervous system is composed of excitatory and inhibitory neurons. One major class of inhibitory neurons release the neurotransmitter γ‐Aminobutyric acid (GABA). GABAergic inhibitory activity maintains the balance that is disrupted in conditions such as epilepsy. At least some GABAergic neurons are initially excitatory and undergo a developmental conversion to convert to inhibitory neurons. The mechanism(s) behind this conversion are thought to include a critical developmental increase in excitatory activity. To test this hypothesis, we subjected ex vivo developing neuronal networks on multi‐electrode arrays to various stimulation and pharmacological regimens. Synaptic activity of networks initially consists of epileptiform‐like high‐amplitude individual "spikes", which convert to organized bursts of activity over the course of approximately 1 month. Stimulation of networks with a digitized synaptic signal for 5 days hastened the decrease of epileptiform activity. By contrast, stimulation for a single day delayed the appearance of bursts and instead increased epileptiform signaling. GABA treatment reduced total signals in unstimulated networks and networks stimulated for 5 days, but instead increased signaling in networks stimulated for 1 day. This increase was prevented by co‐treatment with (2 R )‐amino‐5‐phosphonopentanoate and 6‐cyano‐7‐nitroquinoxaline‐2, 3‐dione, confirming that GABA invoked excitatory activity in networks stimulated for 1 day. Glutamate increased signals in networks subjected to all stimulation regimens; the GABA receptor antagonist bicuculline prevented this increase only in networks stimulated for 1 day. These latter findings are consistent with the induction of so‐called "mixed" synapses (which release a combination of excitatory and inhibitory neurotransmitters) in networks stimulated for 1 day, and support the hypothesis that a critical level of excitatory activity fosters the developmental transition of GABAergic neurons from excitatory to inhibitory.