Glycine neurotransmission: Its role in development (original) (raw)
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Molecular biology of glycinergic neurotransmission
Molecular Neurobiology, 1997
Glycine is a major inhibitory neurotransmitter in the spinal cord and brainstem of vertebrates. Glycine is accumulated into synaptic vesicles by a proton-coupled transport system and released to the synaptic cleft after depolarization of the presynaptic terminal. The inhibitory action of glycine is mediated by pentameric glycine receptors (GlyR) that belong to the ligand-gated ion channel superfamily. The synaptic action of glycine is terminated by two sodium-and chloridecoupled transporters, GLYT1 and GLYT2, located in the glial plasma membrane and in the presynaptic terminals, respectively. Dysfunction of inhibitory glycinergic neurotransmission is associated with several forms of inherited mammalian myoclonus. In addition, glycine could participate in excitatory neurotransmission by modulating the activity of the NMDA subtype of glutamate receptor.
Biochemical and Biophysical Research Communications, 2012
Glycine serves as a neurotransmitter in spinal cord and brain stem, where it activates inhibitory glycine receptors. In addition, it serves as an essential co-agonist of excitatory N-methyl-d-aspartate receptors. In the central nervous system, extracellular glycine concentrations are regulated by two specific glycine transporters (GlyTs), GlyT1 and GlyT2. Here, we determined the relative transport activities and protein levels of GlyT1 and GlyT2 in membrane preparations from mouse brain stem and spinal cord at different developmental stages. We report that early postnatally (up to postnatal day P5) GlyT1 is the predominant transporter isoform responsible for a major fraction of the GlyT-mediated [(3)H]glycine uptake. At later stages (≥ P10), however, the transport activity and expression of GlyT2 increases, and in membrane fractions from adult mice both GlyTs contribute about equally to glycine uptake. These alterations in the activities and expression profiles of the GlyTs suggest that the contributions of GlyT1 and GlyT2 to the regulation of extracellular glycine concentrations at glycinergic synapses changes during development.
Cerebral Cortical Circuitry Formation Requires Functional Glycine Receptors
Cerebral Cortex, 2016
The development of the cerebral cortex is a complex process that requires the generation, migration, and differentiation of neurons. Interfering with any of these steps can impair the establishment of connectivity and, hence, function of the adult brain. Neurotransmitter receptors have emerged as critical players to regulate these biological steps during brain maturation. Among them, α2 subunit-containing glycine receptors (GlyRs) regulate cortical neurogenesis and the present work demonstrates the long-term consequences of their genetic disruption on neuronal connectivity in the postnatal cerebral cortex. Our data indicate that somatosensory cortical neurons of Glra2 knockout mice (Glra2KO) have more dendritic branches with an overall increase in total spine number. These morphological defects correlate with a disruption of the excitation/inhibition balance, thereby increasing network excitability and enhancing susceptibility to epileptic seizures after pentylenetetrazol tail infusion. Taken together, our findings show that the loss of embryonic GlyRα2 ultimately impairs the formation of cortical circuits in the mature brain.
Glycine as a neurotransmitter in the forebrain: a short review
Journal of neural transmission (Vienna, Austria : 1996), 2009
Since the late 1970s glycine has been considered an important inhibitory neurotransmitter in brain stem and medulla. The description of its involvement in the mechanism of action of the potent neurotoxin strychnine pushed further the concept of inhibitory transmitter. The significant concentrations of glycine in forebrain motivated investigators to evaluate different aspects of glycinergic transmission under the ontogenetic, physiologic and pathologic standpoints. This review encompasses a few of these aspects as the role of the different glycine receptors (GlyRs) in intracellular chloride balance, glycine transporters, GABA/Glycine co-release, glycine/NMDA receptor interaction, glycine receptors in acute alcohol effects and advocates a more relevant role for glycine as a stimulatory transmitter in forebrain areas. Finally, the possible co-release of glycine and GABA is considered as an important process to understand the role of glycine in forebrain neural transmission.
Development of synaptic inhibition in glycine transporter 2 deficient mice
Molecular and Cellular Neuroscience, 2010
Mice deficient for the neuronal glycine transporter subtype 2 (GlyT2) die during the second postnatal week after developing neuromotor deficiencies, which resembles severe forms of human hyperekplexia. This phenotype has been attributed to a dramatic reduction in glycinergic neurotransmission. In the present study we analyzed the development of GABAergic and glycinergic synaptic transmission in GlyT2-knockout mice during early postnatal life. Anti-glycine immunohistochemistry in spinal cord and brainstem slices and whole-cell voltage-clamp recordings of glycinergic inhibitory postsynaptic currents (IPSCs) from hypoglossal motoneurons revealed strikingly reduced levels of synaptic glycine already at birth. Since GABA and glycine use the same vesicular inhibitory amino acid transporter (VIAAT or VGAT) we also analysed GABAergic neurotransmission. No increase of GABA immunoreactivity was observed in the spinal cord and brainstem of GlyT2(-/-) mice at any stage of postnatal development. Correspondingly no up-regulation of GABAergic IPSCs was detected in GlyT2(-/-) hypoglossal motoneurons. These data suggest that in the first postnatal week, loss of the glycine transporter 2 is neither compensated by glycine de-novo synthesis nor by up-regulation of the GABAergic transmission in GlyT2(-/-) mice.
The glycine transporter GLYT2 is a reliable marker for glycine-immunoreactive neurons
Molecular Brain Research, 1997
The glycine transporter GLYT2 is present in neurons of the spinal cord, the brain stem and the cerebellum. This localization is similar to that of glycine immunoreactivity, suggesting a causal relationship between GLYT2 expression and glycine distribution. In this report, we analyzed if such a relationship does exist by using neuronal cultures derived from embryonic spinal cord. GLYT2 was synthesized in a small subpopulation of neurons where it was targeted both to dendrites and to axons, being the axonal content higher than the dendritic one. At early stages in the development of cultured spinal neurons, the highest GLYT2 levels were found in the axonal growth cones. As the culture matured, immunoreactivity extended to the axonal shaft. Double-immunofluorescence experiments indicated a perfect co-localization of GLYT2 and glycine immunoreactivity in cultured neurons. Moreover, the concentration of glycine into neurons expressing GLYT2 was proportional to the concentration of the transporter. This observation was reproduced in GLYT2-transfected COS cells. These evidences indicate that the high content of glycine observed in some neurons in culture is indeed achieved by the concentrative task performed by GLYT2, and that GLYT2 can be used as a reliable marker for identification of glycine-enriched neurons. q 1997 Elsevier Science B.V.
Characteristics of glycine receptors expressed by embryonic rat brain mRNAs
Proceedings of The National Academy of Sciences, 2001
A study was made of glycine (Gly) and ␥-aminobutyric acid (GABA) receptors expressed in Xenopus oocytes injected with rat mRNAs isolated from the encephalon, midbrain, and brainstem of 18-dayold rat embryos. In oocytes injected with encephalon, midbrain, or brainstem mRNAs, the Gly-current amplitudes (membrane current elicited by Gly; 1 mM Gly) were respectively 115 ؎ 35, 346 ؎ 28, and 389 ؎ 22 nA, whereas the GABA-currents (1 mM GABA) were all <40 nA. Moreover, the Gly-currents desensitized faster in oocytes injected with encephalon or brainstem mRNAs. The EC 50 for Gly was 611 ؎ 77 M for encephalon, 661 ؎ 28 M for midbrain, and 506 ؎ 18 M for brainstem mRNA-injected oocytes, and the corresponding Hill coefficients were all Ϸ2. Strychnine inhibited all of the Gly-currents, with an IC50 of 56 ؎ 3 nM for encephalon, 97 ؎ 4 nM for midbrain, and 72 ؎ 4 nM for brainstem mRNAs. During repetitive Gly applications, the Gly-currents were potentiated by 1.6-fold for encephalon, 2.1-fold for midbrain, and 1.
Brain Research, 2012
homomers or α-β heteromers. Four out of five subunits; α1-3 and β, have been found in the mammalian brain. Early studies investigating subunit composition and expression patterns of this receptor have proposed a developmental switch from α2 homomers to α1β heteromers as the CNS matures, a conclusion primarily based on results from the spinal cord. However, our previous results indicate that this might not apply to e.g. the forebrain regions. Here we examined alterations in GlyR expression caused by developmental changes in selected brain areas, focusing on reward-related regions. Animals of several ages (P2, P21 and P60) were included to examine potential changes over time. In accordance with previous reports, a switch in expression was observed in the spinal cord. However, the present results indicate that a decrease in α2 subunit expression is not replaced by α1 subunit expression since the generally low levels, and modest increases, of α1 could hardly replace the reduction in α2-mRNA. Instead mRNA measurements indicate that α2 continues to be the dominating α-subunit also in adult animals, usually in combination with high and stable levels of β-subunit expression. This indicates that alterations in GlyR subunit expression are not simply a maturation effect common for the entire CNS, but rather a unique pattern of transition depending on the region at hand.