Abstract
Homeostatic control of neuronal excitability by modulation of synaptic inhibition (I) and excitation (E) of the principal neurons is important during brain maturation. The fundamental features of in-utero brain development, including local synaptic E–I ratio and bioenergetics, can be modeled by cerebral organoids (CO) that have exhibited highly regular nested oscillatory network events. Therefore, we evaluated a 'Phase Zero' clinical study platform combining broadband Vis/near-infrared(NIR) spectroscopy and electrophysiology with studying E–I ratio based on the spectral exponent of local field potentials and bioenergetics based on the activity of mitochondrial Cytochrome-C Oxidase (CCO). We found a significant effect of the age of the healthy controls iPSC CO from 23 days to 3 months on the CCO activity (chi-square (2, N = 10) = 20, p = 4.5400e−05), and spectral exponent between 30–50 Hz (chi-square (2, N = 16) = 13.88, p = 0.001). Also, a significant effect of drugs, choline (CHO), idebenone (IDB), R-alpha-lipoic acid plus acetyl-l-carnitine (LCLA), was found on the CCO activity (chi-square (3, N = 10) = 25.44, p = 1.2492e−05), spectral exponent between 1 and 20 Hz (chi-square (3, N = 16) = 43.5, p = 1.9273e−09) and 30–50 Hz (chi-square (3, N = 16) = 23.47, p = 3.2148e−05) in 34 days old CO from schizophrenia (SCZ) patients iPSC. We present the feasibility of a multimodal approach, combining electrophysiology and broadband Vis–NIR spectroscopy, to monitor neurodevelopment in brain organoid models that can complement traditional drug design approaches to test clinically meaningful hypotheses.
Highlights
Homeostatic control of neuronal excitability by modulation of synaptic inhibition (I) and excitation (E) of the principal neurons during brain maturation is important to avoid runaway excitability conditions[1]
Since calretinin interneurons play a crucial role in the generation of synchronous, rhythmic neuronal activity by interacting with other interneurons[34]; we investigated the E–I ratio in conjunction with Cytochrome-C Oxidase (CCO) activity in the cerebral organoids from schizophrenia patients and healthy controls
The spectral exponent in the 30–50 Hz frequency band was most responsive to the drug treatment. In this proof-of-concept study, we showed the feasibility of a ’Phase Zero’ clinical study platform to investigate changes in the E–I ratio based on the spectral exponent of local field potentials (LFPs) in conjunction with changes in the bioenergetics based on the mitochondrial CCO activity
Summary
Homeostatic control of neuronal excitability by modulation of synaptic inhibition (I) and excitation (E) of the principal neurons during brain maturation is important to avoid runaway excitability conditions[1]. We leveraged partial least square processing of the Vis–NIR spectra using redox calibration data for the quantification of CCO activity in the cerebral organoids In this proof-of-concept ’Phase Zero’ study, we investigated CCO activity in the cerebral organoids during the initial phase of healthy neurodevelopment, where a decrease in the E–I ratio was expected[1]. Since calretinin interneurons play a crucial role in the generation of synchronous, rhythmic neuronal activity by interacting with other interneurons[34]; we investigated the E–I ratio in conjunction with CCO activity in the cerebral organoids from schizophrenia patients and healthy controls. In this proof-of-concept study, we investigated the feasibility of capturing drug effects of C HO38, IDB39, and L CLA36,40, on cerebral organoids from schizophrenia patients using a ’Phase Zero’ clinical study platform
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