Insufficient developmental excitatory neuronal activity fails to foster establishment of normal levels of inhibitory neuronal activity. Issue 55 (December 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: 2016-12
• 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

Highlights: We subjected ex vivo developing neuronal networks on multi-electrode arrays to various stimulation and pharmacological regimens. Ex vivo networks initially display high-amplitude, epileptiform activity, which converts 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 appearance of organized bursts. 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. 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.