Developmental changes in the expression of GABAA receptor alpha 1 and gamma 2 subunits in human temporal lobe, hippocampus and basal ganglia: An implication for consideration on age-related epilepsy

Kanaumi, Takeshi; Takashima, Sachio; Iwasaki, Hiroshi; Mitsudome, Akihisa; Hirose, Shinichi

doi:10.1016/j.eplepsyres.2006.05.019

Cited by 28 publications

(23 citation statements)

References 19 publications

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“…Consistent with our observation, ␥ subunit-containing benzodiazepine-sensitive GABA A Rs are important for the development of hindbrain neural networks at E4-5 in the chick (18,19). Likewise it is emerging that mammalian neuroblast production and their subsequent differentiation is also regulated by benzodiazepine-sensitive GABA A Rs and the ␥2 subunit is expressed early during embryonic development in rats and humans (20)(21)(22)23). …”

Section: Discussionsupporting

confidence: 72%

Deficits in spatial memory correlate with modified γ-aminobutyric acid type A receptor tyrosine phosphorylation in the hippocampus

Tretter

Revilla-Sanchez

Houston

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Fast synaptic inhibition in the brain is largely mediated by ␥-aminobutyric acid receptors (GABAAR). While the pharmacological manipulation of GABAAR function by therapeutic agents, such as benzodiazepines can have profound effects on neuronal excitation and behavior, the endogenous mechanisms neurons use to regulate the efficacy of synaptic inhibition and their impact on behavior remains poorly understood. To address this issue, we created a knock-in mouse in which tyrosine phosphorylation of the GABAARs ␥2 subunit, a posttranslational modification that is critical for their functional modulation, has been ablated. These animals exhibited enhanced GABAAR accumulation at postsynaptic inhibitory synaptic specializations on pyramidal neurons within the CA3 subdomain of the hippocampus, primarily due to aberrant trafficking within the endocytic pathway. This enhanced inhibition correlated with a specific deficit in spatial object recognition, a behavioral paradigm dependent upon CA3. Thus, phospho-dependent regulation of GABAAR function involving just two tyrosine residues in the ␥2 subunit provides an input-specific mechanism that not only regulates the efficacy of synaptic inhibition, but has behavioral consequences.cognition ͉ GABAA receptor ͉ inhibitory synapses G ABA A Rs are the principal sites of fast synaptic inhibition in the adult brain and are the therapeutic sites of action for benzodiazepines and barbiturates (1, 2). In the adult brain, the majority of benzodiazepine synaptic GABA A R subtypes are hetero-pentamers that are primarily assembled from ␣1-3, ␤1-3, and ␥2 subunits (1, 2). A critical determinant for the efficacy of synaptic inhibition is the number of GABA A Rs that are present at inhibitory postsynaptic sites, a process that is subject to dynamic modulation via the phosphorylation of residues within the intracellular domains of individual receptor subunits (3-5, 6, 7). In vitro experiments have revealed that phosphorylation modulates both channel kinetics and receptor membrane trafficking, however the role of GABA A R phosphorylation in shaping the efficacy of synaptic inhibition and affecting behavior remain unknown (5).To begin to explore this issue, we have created a knock-in mouse in which the principal sites of tyrosine phosphorylation within GABA A Rs, residues Y365 and Y367 within the ␥2 subunit, have been mutated to phenylalanines. The resulting animal model provides clear evidence that GABA A R phosphorylation regulates the efficacy of synaptic inhibition by modulating their membrane trafficking in the endocytic pathway in the brain and also influences some aspects of hippocampal-dependent cognition. Results Mutation of Tyrosine Phosphorylation in the ␥2 Subunit Results inEmbryonic Lethality. To explore the role that phosphorylation of GABA A Rs plays in determining the efficacy of synaptic inhibition, we created a mouse in which the principal sites of tyrosine phosphorylation with the ␥2 subunit gene were mutated to phenylalanines (Y365/7F) (Fig. 1A). Linearized DNA was used to ele...

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Section: Discussionsupporting

confidence: 72%

Deficits in spatial memory correlate with modified γ-aminobutyric acid type A receptor tyrosine phosphorylation in the hippocampus

Tretter

Revilla-Sanchez

Houston

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…In children and adults, GABA mediates the majority of fast inhibitory neurotransmission in the central nervous system through its activation of the GABAA receptor. However, both the subunit composition neuronal GABA a receptors and functional role changes during prenatal and postnatal development in humans (Andersen et al, 2002; Brooks-Kayal and Pritchett 1993; Kanaumi, et al, 2006; Reichelt et al, 1991). Due to elevated intracellular Cl- concentrations in immature neurons, GABA signaling in neonatal brain acts as an excitatory neurotransmitter – which switches to an inhibitory neurotransmitter after about the first 2 years of life (Jansen et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Functional and structural correlates of the aging brain: Relating visual cortex (V1) gamma band responses to age‐related structural change

Gaetz

Roberts

Singh

et al. 2011

Human Brain Mapping

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The gamma band response is thought to be a key neural signature of information processing in the mammalian brain, yet little is known about how age-related maturation influences the gamma-band response. Recent MRI based studies have shown that brain maturation is accompanied by clear structural changes in both grey and white matter, yet the correspondence of these changes to brain function is unclear. The objective of this study was to relate visual cortex (V1) gamma-band responses to age-related structural change. We evaluated MEG measured gamma-band responses to contrast gratings stimuli and structural MRIs from participants observed from 2 separate research centers (MEG lab at CUBRIC, Cardiff University, UK, and the Lurie Family Foundations MEG Imaging Center, (CHOP) at the Children’s Hospital of Philadelphia). Pooled participant data (N=59) ranged in age from 8.7 to 45.3 yrs. We assessed linear associations between age and MEG gamma-band frequency and amplitude, as well as between age and MRI volumetric parameters of the occipital lobe. Our MEG findings revealed a significant negative correlation for gamma band frequency vs. age. Volumetric brain analysis from the occipital lobe also revealed significant negative correlations between age and the cortical thickness of pericalcarine and cuneus areas. Our functional MEG and structural MRI findings shows regionally specific changes due to maturation and may thus be informative for understanding physiological processes of neural development, maturation, and age-related decline. In addition, this study represents (to our knowledge), the first published demonstration of multi-centre data sharing across MEG centers.

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“…In contrast, in the current study, the expression levels of α1 and α2 subunits progressively changed with age, including significant differences between prepubertal and adult animals, indicating that the developmental regulation of α1 and α2 subunit expression is quite protracted, extending through adolescence in primate DLPFC. However, in the hippocampus and entorhinal cortex, α1 subunit expression is reported to be high in both neonatal rodents and primates (34–36), indicating that the timing of developmental changes in α1 and α2 subunit expression might differ across cortical areas.…”

Section: Discussionmentioning

confidence: 99%

Protracted Developmental Trajectories of GABAA Receptor α1 and α2 Subunit Expression in Primate Prefrontal Cortex

Hashimoto¹,

Nguyen²,

Rotaru³

et al. 2009

Biological Psychiatry

140

113

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Background In schizophrenia, working memory dysfunction is associated with altered expression of gamma-aminobutyric acid (GABA)A receptor α1 and α2 subunits in the dorsolateral prefrontal cortex (DLPFC). In rodents, cortical α subunit expression shifts from low α1 and high α2 to high α1 and low α2 during early postnatal development. Because these two α subunits confer different functional properties to the GABAA receptors containing them, we determined whether this shift in α1 and α2 subunit expression continues through adolescence in the primate DLPFC, potentially contributing to the maturation of working memory during this developmental period. Methods Levels of GABAA receptor α1 and α2 subunit mRNAs were determined in the DLPFC of monkeys aged 1 week, 4 weeks, 3 months, 15–17 months (prepubertal), and 43–47 months (postpubertal) and in adult monkeys using in situ hybridization, followed by the quantification of α1 subunit protein by western blotting. We also performed whole-cell patch clamp recording of miniature inhibitory postsynaptic potentials (mIPSPs) in DLPFC slices prepared from pre- and postpubertal monkeys. Results The mRNA and protein levels of α1 and α2 subunits progressively increased and decreased, respectively, throughout postnatal development including adolescence. Furthermore, as predicted by the different functional properties of α1-containing versus α2-containing GABAA receptors, the mIPSP duration was significantly shorter in postpubertal than in prepubertal animals. Conclusions In contrast to rodents, the developmental shift in GABAA receptor α subunit expression continues through adolescence in primate DLPFC, inducing a marked change in the kinetics of GABA neurotransmission. Disturbances in this shift might underlie impaired working memory in schizophrenia.

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Developmental changes in the expression of GABAA receptor alpha 1 and gamma 2 subunits in human temporal lobe, hippocampus and basal ganglia: An implication for consideration on age-related epilepsy

Cited by 28 publications

References 19 publications

Deficits in spatial memory correlate with modified γ-aminobutyric acid type A receptor tyrosine phosphorylation in the hippocampus

Deficits in spatial memory correlate with modified γ-aminobutyric acid type A receptor tyrosine phosphorylation in the hippocampus

Functional and structural correlates of the aging brain: Relating visual cortex (V1) gamma band responses to age‐related structural change

Protracted Developmental Trajectories of GABAA Receptor α1 and α2 Subunit Expression in Primate Prefrontal Cortex

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