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GABA from reactive astrocytes impairs memory in mouse models of Alzheimer's disease
Jo, Seonmi,Yarishkin, Oleg,Hwang, Yu Jin,Chun, Ye Eun,Park, Mijeong,Woo, Dong Ho,Bae, Jin Young,Kim, Taekeun,Lee, Jaekwang,Chun, Heejung,Park, Hyun Jung,Lee, Da Yong,Hong, Jinpyo,Kim, Hye Yun,Oh, Soo- Nature Publishing Group, a division of Macmillan P 2014 Nature medicine Vol.20 No.8
In Alzheimer's disease (AD), memory impairment is the most prominent feature that afflicts patients and their families. Although reactive astrocytes have been observed around amyloid plaques since the disease was first described, their role in memory impairment has been poorly understood. Here, we show that reactive astrocytes aberrantly and abundantly produce the inhibitory gliotransmitter GABA by monoamine oxidase-B (Maob) and abnormally release GABA through the bestrophin 1 channel. In the dentate gyrus of mouse models of AD, the released GABA reduces spike probability of granule cells by acting on presynaptic GABA receptors. Suppressing GABA production or release from reactive astrocytes fully restores the impaired spike probability, synaptic plasticity, and learning and memory in the mice. In the postmortem brain of individuals with AD, astrocytic GABA and MAOB are significantly upregulated. We propose that selective inhibition of astrocytic GABA synthesis or release may serve as an effective therapeutic strategy for treating memory impairment in AD.
Yarishkin, Oleg,Lee, Jaekwang,Jo, Seonmi,Hwang, Eun Mi,Lee, C. Justin The Korean Society for Brain and Neural Science 2015 Experimental Neurobiology Vol.24 No.3
<P>Like neurons, astrocytes produce and release GABA to influence neuronal signaling. At the perforant path to dentate gyrus granule neuron synapse, GABA from astrocyte was found to be a strong inhibitory factor, which impairs synaptic transmission, synaptic plasticity and memory in Alzheimer's disease. Although astrocytic GABA is observed in many brain regions, its physiological role has not been clearly demonstrated yet. Here, we show that astrocytic GABA exerts disinhibitory action to dentate granule neurons by targeting GABA<SUB>B</SUB> receptors of GABAergic interneurons in wild-type mice. This disinhibitory effect is specific to a low intensity of electrical stimulation at perforant path fibers. Inversely in Alzheimer's disease model mice, astrocytic GABA targets GABA<SUB>A</SUB> receptors and exerts inhibitory action by reducing release probability of glutamatergic perforant path terminals. These results suggest that astrocytic GABA differentially modulates the signaling from cortical input to dentate gyrus under physiological and pathological conditions.</P>
Glial GABA, synthesized by monoamine oxidase B, mediates tonic inhibition
Yoon, Bo‐,Eun,Woo, Junsung,Chun, Ye‐,Eun,Chun, Heejung,Jo, Seonmi,Bae, Jin Young,An, Heeyoung,Min, Joo Ok,Oh, Soo‐,Jin,Han, Kyung‐,Seok,Kim, Hye Yun,Kim, Taekeun,Kim, Young Soo Cambridge University Press 2014 The Journal of physiology Vol.592 No.22
<P><B></B></P><P>GABA is the major inhibitory transmitter in the brain and is released not only from a subset of neurons but also from glia. Although neuronal GABA is well known to be synthesized by glutamic acid decarboxylase (GAD), the source of glial GABA is unknown. After estimating the concentration of GABA in Bergmann glia to be around 5–10 m<SMALL>m</SMALL> by immunogold electron microscopy, we demonstrate that GABA production in glia requires MAOB, a key enzyme in the putrescine degradation pathway. In cultured cerebellar glia, both Ca<SUP>2+</SUP>‐induced and tonic GABA release are significantly reduced by both gene silencing of MAOB and the MAOB inhibitor selegiline. In the cerebellum and striatum of adult mice, general gene silencing, knock out of MAOB or selegiline treatment resulted in elimination of tonic GABA currents recorded from granule neurons and medium spiny neurons. Glial‐specific rescue of MAOB resulted in complete rescue of tonic GABA currents. Our results identify MAOB as a key synthesizing enzyme of glial GABA, which is released via bestrophin 1 (Best1) channel to mediate tonic inhibition in the brain.</P>
Kim, Jeongjin,Woo, Jeonghoon,Park, Young-Gyun,Chae, Sujin,Jo, Seonmi,Choi, Jeong Woo,Jun, Hong Young,Yeom, Young Il,Park, Seong Hoon,Kim, Kyung Hwan,Shin, Hee-Sup,Kim, Daesoo The Society 2011 The Journal of neuroscience Vol.31 No.11
<P>Hypoxic damage to the prefrontal cortex (PFC) has been implicated in the frontal lobe dysfunction found in various neuropsychiatric disorders. The underlying subcortical mechanisms, however, have not been well explored. In this study, we induced a PFC-specific hypoxia-like damage by cobalt-wire implantation to demonstrate that the role of the mediodorsal thalamus (MD) is critical for the development of frontal lobe dysfunction, including frontal lobe-specific seizures and abnormal hyperactivity. Before the onset of these abnormalities, the cross talk between the MD and PFC nuclei at theta frequencies was enhanced. During the theta frequency interactions, burst spikes, known to depend on T-type Ca(2+) channels, were increased in MD neurons. In vivo knockout or knockdown of the T-type Ca(2+) channel gene (Ca(V)3.1) in the MD substantially reduced the theta frequency MD-PFC cross talk, frontal lobe-specific seizures, and locomotor hyperactivity in this model. These results suggest a two-step model of prefrontal dysfunction in which the response to a hypoxic lesion in the PFC results in abnormal thalamocortical feedback driven by thalamic T-type Ca(2+) channels, which, in turn, leads to the onset of neurological and behavioral abnormalities. This study provides valuable insights into preventing the development of neuropsychiatric disorders arising from irreversible PFC damage.</P>
An, Hye Suck,Han, Jong Won,Hwang, Hyun-Ju,Jeon, Hancheol,Jung, Seung-Hyun,Jo, Seonmi,Choi, Tae-Young,Hyun, Young Se,Song, Ha Yeun,Whang, Ilson The Korean Society of Marine Life Science 2017 한국해양생명과학회지 Vol.2 No.2
In abalones, interspecific hybridization has been suggested as a possible means to increase production and desired traits for the industry. In Korea, Haliotis gigantea is considered a species with a larger size and higher temperature tolerance than H. discus hannai. However, H. discus hannai is considered the most valuable and popular fishery resource due to its better acceptance and higher market prices. Thus, viable interspecific hybrids have been produced by artificial inseminating H. gigantea eggs with H. discus hannai sperm. However, the reciprocal hybrid cross was not successful. In this study, the hybridity and the growth and thermal tolerance performance of the interspecific hybrids were examined. A combination of various assays revealed maximum growth occurrence at 21℃ and the higher growth rate in the hybrids than that of H. discus hannai parent. In addition, the growth and survival at high-temperature (28℃) of the hybrids was equivalent to that of the highly tolerant H. gigantea parent, suggesting new possibilities to overcome the mass mortality in H. discus hannai during high temperature periods of summer season in Korea. Furthermore, the induced interspecific hybrid status was confirmed by the presence of species-specific bands for each parental species of the random amplified polymorphic DNA (RAPD) profiles using universal rice primer (URP), which could be used as speciesspecific markers to distinguish the hybrids and their parental species.