Distinct α subunits of the GABAA receptor are responsible for early hippocampal silent neuron‐related activities
Giuseppina GiusiRosa Maria FaccioloMaria RendeRaffaella AlóAnna Di VitoSimona SalernoSabrina MorelliLoredana De BartoloEnrico DrioliMarcello Canonaco
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Abstract The modulatory actions of GABA A receptor subunits are crucial for morphological and transcriptional neuronal activities. In this study, growth of hamster hippocampal neurons on biohybrid membrane substrates allowed us to show for the first time that the two major GABA A α receptor subunits (α 2,5 ) are capable of early neuronal shaping plus expression differences of some of the main neuronal cytoskeletal factors (GAP‐43, the neurotrophin––BDNF) and of Gluergic subtypes. In a first case the inverse α 5 agonist (RY‐080) seemed to account for the reduction of dendritic length at DIV7, very likely via lower BDNF levels. Conversely, the effects of the preferentially specific agonist for hippocampal α 2 subunit (flunitrazepam) were, instead, directed at the formation of growth cones at DIV3 in the presence of greatly ( P < 0.01) diminished GAP‐43 levels as displayed by strongly reduced axonal sprouting. It is interesting to note that concomitantly to these morphological variations, the transcription of some Gluergic receptor subtypes resulted to be altered. In particular, flunitrazepam was responsible for a distinctly rising expression of axonal NR1 mRNA levels from DIV3 ( P < 0.01) until DIV7 ( P < 0.001), whereas RY‐080 evoked a very great ( P < 0.001) downregulation of dendritic GluR2 at only DIV7. Together, our results demonstrate that GABA A α 2,5 receptor‐containing subunits by regulating the precise synchronization of cytoskeletal factors are considered key modulating neuronal elements of hippocampal morphological growth features. Moreover, the notable NR1 and GluR2 transcription differences promoted by these GABA A α subunits tend to favorably corroborate the early role of α 2 + α 5 on hippocampal neuronal networks in hibernating rodents through the recruitment and activation of silent neurons, and this may provide useful insights regarding molecular neurodegenerative events. © 2009 Wiley‐Liss, Inc.As key factors in the development and maintenance of the auditory system, neurotrophins can prevent auditory neuron degeneration when applied within three to five days of deafening. We tested each of the neurotrophins BDNF, NT-3, NT-4/5 and NGF for their ability to support auditory neuron survival following a two-week period of deafness in guinea pigs, when ∼15% auditory neuron degeneration has already occurred. Although delayed, the treatment with each neurotrophin prevented further degeneration with similar efficacy.
Neurotrophin-3
Degeneration (medical)
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硬膜外鎮痛法は周術期や慢性･急性疼痛の管理に有意義である. 使用される薬剤はモルヒネが主流であるが, さまざまな薬剤が試用され, その評価もさまざまである. 硬膜外投与された薬剤は拡散して脊髄に作用するため, 血液脳関門は関与しない. 脊髄には多数のμおよびκ受容体が発現しているが, モルヒネなどのμ作動薬に比較してκ作動薬は副作用が少なく, 安全性が高い. それ故, 硬膜外κ作動薬は有意義な鎮痛法であり, 全身の鎮痛 (頭部･顔面に対しては頸部硬膜外鎮痛で可能) に応用できる. 一方, NMDA拮抗薬は, 痛覚過敏や中枢性感作などの疼痛の促通･増幅を抑制し (鎮痛とは異なる) , オピオイドとの相乗作用や耐性･依存性抑制作用がある (オピオイドの補助薬としての適応) . しかし, 一次求心性インパルスをブロックしないためNMDA拮抗薬に脊髄性鎮痛作用は期待できない. 全身投与によるNMDA拮抗薬は上位中枢神経系の統合機序に影響すると考えられ, 中枢痛･視床痛などには効果が期待できる. しかし, 硬膜外NMDA拮抗薬の効果は脊髄に限られるので, 全身投与に優る効果は期待できない. ケタミンについて考えると, この薬剤は作用特異性が低く, 多彩な効果が期待できる. これにより, 大量投与で全身麻酔作用が, 少量投与で鎮痛作用が現われると考えられる.
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E. Kochs Institut für Anaesthesiologie der Technischen Universität München, Ismaninger Str 22, D-81675 Munich, Germany
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N-methyl-D-aspartate(NMDA) 수용체는 중추신경계의 대표적 흥분성 신경전달물질인 glutamate의 수용체 중 하나로, NMDA 수용체 기본단위들의 발현 상태나 위치, 활동 정도에 따라서 수많은 신경학적, 정신적인 상태가 결정 될 수 있다. 많은 신경정신 질환들은 시냅스의 결함, 특히 NMDA수용체의 기능 장애가 그 원인으로 지목되고 있다. NMDA 수용체의 과잉활성뿐만 아니라 활동저하 역시 신경학적인 변화를 초래할 수 있기 때문에 NMDA 수용체 길항제와 부분효능제가 중추신경계 관련 질환의 치료제로 사용되고 있다. Glutamate의 증가는 뇌 관련 질환을 일으키거나 신경세포의 사멸을 초래하기 때문에 NMDA 수용체의 길항제가 이와 관련된 치료제가 될 가능성이 있다. 또한 지속적인 glutamate의 증가는 파킨슨병이나 알츠하이머병과 같은 퇴행성 신경질환을 야기하기도 한다. 동물 실험에서 NMDA 수용체 길항제가 허혈성 뇌 손상이나 외상적인 손상에 대해 신경보호 효과를 보여주는 것이 이를 뒷받침해준다. 그러나 NMDA 수용체를 구성하는 기본단위들에 대한 선택적인 약물들이 아닌 광범위한 길항제들은 부작용을 일으키고 치료효과가 높지 않다는 한계가 있다. 따라서 이러한 기본 단위들에 대한 선택적인 길항제에 대한 연구나 기본단위들의 발현 정도를 연구해야 할 필요성이 대두되고 있다. NMDA 수용체의 기본 단위는 세 가지 종류로 GluN1, GluN2(GluN2A, GluN2B, GluN2C, GluN2D), luN3(GluN3A,GluN3B)가 있으며, 전형적으로 GluN1과 GluN2의 결합으로 NMDA 수용체를 이룬다. NMDA 수용체 기본단위의 여러 조합은 중추신경계의 수용체가 다양성을 이루게 해주며 이러한 기본단위들의 조합과 발현 정도에 따라 NMDA 수용체의 기능이 결정 된다. 따라서 기본단위들의 조합이 NMDA 수용체의 조절능력의 중요한 요인이 되며 기본단위의 발현상태가 달라지면 NMDA 수용체의 기능이상이 생길 수 있다. 많은 중추신경계질환들에서 이러한 기본단위의 변화로 인한 NMDA 수용체의 기능이상이 원인으로 지목되고 있다. 이러한 중추신경계 질환들에 대한 연구는 대부분 NMDA수용체의 기본단위 중 가장 많은 부분을 차지 하는 GluN2의 변화에 초점이 맞춰져 있다. GluN3A의 경우 조현병에 영향이 있다는 연구결과가 보고 되었으나, 신경정신학적 질병들에 대한 연구가 GluN2에 비해 많이 진행되고 있지 않다.GRIN3A는 GluN3A를 암호화하는 유전자로서 GluN3A는 다른 NMDA 수용체의 기본단위들 보다 적은 부분을 차지하지만 시냅스의 발달에 관여하는 것으로 보고되고 있고, GluN3A의 증가는 NMDA 수용체의 기능을 저하시키는 것으로 알려져있다. 본 연구진은 사전 연구에서 GRIN3A가 주의력 결핍 과잉행동 장애 동물 모델인 본태성 고혈압 쥐에서 현저히 낮게 발현되는 것을 확인하였다.이를 통해 GluN3A가 신경정신학적 관련 질병에 기여 할 수 있다고 예측되는바 본 연구에서는 GRIN3A의 유전자 조작 마우스를 사용하여 GluN3A가 신경정신계에 어떤 영향을 미치는지 밝히고자 하였다.N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that play a significant role in synaptic plasticity, learning, memory, and other behaviors. NMDARs are composed of various subunits and display unique properties depending on their subunit composition. The GluN3A subunit is thought to suppress NMDAR activity, however its exact function has not been well studied. Thus, we designed a transgenic mice overexpressing GRIN3A to assess the role of this gene on various behaviors. GRIN3A-overexpressing mice were subjected to an array of behavioral experiments including locomotor activity test, rota-rod test, elevated plus-maze (EPM) test, and Y-maze test. GRIN3A-overexpressing mice displayed hypoactivity but no effects on the rota-rod test, EPM test and Y-maze test. The GRIN3A-overexpressing mice that we have created can be utilized in elucidating the role of the GRIN3A gene and its product, the GluN3A subunit of NMDARs, on various behaviors associated with neuropsychiatric disorders, such as ADHD, and in finding possible therapeutic targets for these disorders.
Phencyclidine
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Hapfelmeier, G.; Haseneder, R.; Scheller, M.; Neumahr, S.; Kochs, E. Author Information
GABAA-rho receptor
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2-Amino-5-phosphonovalerate
Dizocilpine
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The effects of Zn2+ on GABAA-receptor mediated responses in acutely isolated rat sacral dorsal commissural nucleus (SDCN) were studied using nystatin-perforated whole cell recording techniques. The results demonstrated that (1) GABA induced inward currents through activation of GABAA-receptor at a holding potential of -40 mV; (2) GABAA-receptor mediated responses were suppressed by Zn2+ in a reversible and voltage-independent manner; and (3) in the presence of Zn2+, the concentration-response curve of GABA-induced responses was shifted to the right in a parallel manner. The results suggest that Zn2+ allosterically depresses GABAA-receptor mediated currents.
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Gamma-Aminobutyric Acid
GABA receptor
Reversal potential
GABAA-rho receptor
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Effect of liposome entrapped‐GABA on the expression of nNOS and GABAA receptors in neurons (1130.11)
Liposomes are concentric lipid vesicles that allow a sustained release of entrapped substances. GABA is the most prevalent inhibitory neurotransmitter in the central nervous system. Here we determined the effect of sustained release of GABA on the expression of neuronal nitric oxide synthase (nNOS) and GABAA receptor (GABAAR) in a neuronal culture (NG108‐15 cells). GABA entrapped‐liposomes particles (GEL) were prepared by the freeze‐thawing method. In vitro studies using NG108‐15 neurons treated with different doses of GEL for 12 hr showed an increase in nNOS (138, 157 and 165% at doses of 20, 50 and 100 ng respectively) and GABAAR (54 and 50% at the doses of 10 and 20 ng respectively) compared with control. Moreover, we found a decreased expression of protein inhibitor of nNOS (PIN) with GEL treatment (26, 66 and 57% at doses of 20, 50 and 100 ng, respectively). Time course experiments in cells treated with 50 ng of GEL, showed an increase in GABAAR (23%) after 1 hr followed by an increase in nNOS (55, 46 and 55%) and decrease in PIN (22, 28 and 53%) at 8, 12, 24 hr, respectively. Immunostaining also showed an increase in nNOS expression (134%) in cells after 12 hr of GEL treatment. These results suggest that the slow release of GABA can change the expression of nNOS in neuronal cultures, potentially by altering the expression of PIN. Supported by NIH grants HL62222 & DK82956 & CNPq fellowship to GCV. Grant Funding Source : NIH grants HL62222 & DK82956 & CNPq fellowship to GCV
Immunostaining
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Objective To investigate the protective mechanism of Mg2f on neuron. Methods GABAA-re-ceptor mediating responses in cultured rat hippocampal neurons were studied using whole-cell recording techniques. Results (1) GABA induced inward currents through activation of GABAA-receptor at a holding potential of 40mV; (2) GABA_A-receptor mediated responses were enhanced when Mg2+ and GABA used together ; (3) in the presence of Mg2+ , the concentration-response curve of GABA-induced responses was shifted to the left in parallel manner. Conclusion It is implicated that Mg2+ affect the function of GABAA-receptor through positive al-losteric manner. By this manner,it protects the ischemic neurons.
GABA receptor
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Class C GPCR
GABAA-rho receptor
Rhodopsin-like receptors
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