Elevated preoptic brain activity in zebrafish glial glycine transporter mutants is linked to lethargy-like behaviors and delayed emergence from anesthesia

Abstract

Delayed emergence from anesthesia was previously reported in a case study of a child with Glycine Encephalopathy. To investigate the neural basis of this delayed emergence, we developed a zebrafish glial glycine transporter (glyt1 − / −) mutant model. We compared locomotor behaviors; dose–response curves for tricaine, ketamine, and 2,6-diisopropylphenol (propofol); time to emergence from these anesthetics; and time to emergence from propofol after craniotomy in glyt1−/− mutants and their siblings. To identify differentially active brain regions in glyt1−/− mutants, we used pERK immunohistochemistry as a proxy for brain-wide neuronal activity. We show that glyt1−/− mutants initiated normal bouts of movement less frequently indicating lethargy-like behaviors. Despite similar anesthesia dose–response curves, glyt1−/− mutants took over twice as long as their siblings to emerge from ketamine or propofol, mimicking findings from the human case study. Reducing glycine levels rescued timely emergence in glyt1−/− mutants, pointing to a causal role for elevated glycine. Brain-wide pERK staining showed elevated activity in hypnotic brain regions in glyt1−/− mutants under baseline conditions and a delay in sensorimotor integration during emergence from anesthesia. Our study links elevated activity in preoptic brain regions and reduced sensorimotor integration to lethargy-like behaviors and delayed emergence from propofol in glyt1−/− mutants.

NEDD4L-Sp1 ubiquitination inhibits GlyT1 to promote prominent hippocampal neuronal damage and apoptosis, leading to cognitive dysfunction in diabetic rats

“…It is well known that GlyT1 is generally highly expressed in cognitive dysfunction [71,74].Therefore, our study explored the reasons for its decreased expression in diabetic cognitive dysfunction. We used a database to predict that the classical transcription factor Sp1 binds to the GlyT1 promoter region and thus developed our study.…”

Coffin–Siris syndrome and delayed emergence—Is this an unusual or unknown anesthetic complication?

“…There are case reports of delayed emergence from GA with inhalational anesthesia in children with developmental delay, mental retardation, and hypotonia. 3 Propofol suppresses arousal-promoting dopaminergic neurons in the brain and inhibits orexinergic neuron activity. 4 Delayed emergence may be related to abnormal choline-associated activity in the CNS 5 which is important for emergence from propofol anesthesia.…”

“…Propofol is the preferred agent for TIVA for MRI procedures as it maintains spontaneous breathing in patients, allows easy titration for anesthetic depth, rapid recovery from anesthesia, and has an antiemetic effect. There are case reports of delayed emergence from GA with inhalational anesthesia in children with developmental delay, mental retardation, and hypotonia 3 …”

Hypoxia-Induced Cardiac Arrest Alters Central Nervous System Concentrations of the GLYT2 Glycine Transporter in Zebrafish (Danio rerio)

“…This was supported by other research that showed when intracellular glycine concentration would rise, GLYT1 would have the reverse function and release glycine (Huang et al, 2004;Raiteri et al, 2008;Raiteri and Raiteri, 2010). Venincasa et al (2021) analyzed the elevation of zebrafish glial glycine transporter mutants in lethargic-like behaviors and delays in emergence from anesthesia. This was a study done on a patient with glycine encephalopathy, which is an elevated level of glycine that inhibits motor control and suppresses respiration.…”

“…Because of this knockout, with the lack of the GLYT transporter, the zebrafish larvae displayed lethargic-like behaviors, due to their elevated levels of glycine and shows that glycine is inhibitory in larval zebrafish from 5pf. (Venincasa et al, 2021) As a major inhibitory neurotransmitter, glycine has several roles including participation in the processes of motor and sensory information, movement, vision, and audition (Paul, 2000;Lopez-Corcuera et al, 2001). Glycine acts in the synaptic cleft as an inhibitor, and the termination of its actions is believed to be done by the rapid reuptake through two sodium-and-chloridecoupled transporters, GLYT1 and GLYT2, located on either glial cells (astrocytes and radial glial cells) or pre-synaptic terminals (Lopez-Corceura et al, 2001).…”