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Activity-Dependent Bidirectional Regulation of GAD Expression in a Homeostatic Fashion Is Mediated by BDNF-Dependent and Independent Pathways.

Hanno-Iijima Y, Tanaka M, Iijima T - PLoS ONE (2015)

Bottom Line: Additional results indicated that these two GAD genes differ in their responsiveness to chronic changes in neuronal activity, which could be partially caused by differential dependence on BDNF.In parallel to activity-dependent bidirectional scaling in GAD expression, the present study further observed that a chronic change in neuronal activity leads to an alteration in neurotransmitter release from GABAergic neurons in a homeostatic, bidirectional fashion.Therefore, the differential expression of GAD65 and 67 during prolonged changes in neuronal activity may be implicated in some aspects of bidirectional homeostatic plasticity within mature GABAergic presynapses.

View Article: PubMed Central - PubMed

Affiliation: Tokai University Institute of Innovative Science and Technology, Medical Division, Kanagawa, Japan; School of Medicine, Tokai University, Kanagawa, Japan.

ABSTRACT
Homeostatic synaptic plasticity, or synaptic scaling, is a mechanism that tunes neuronal transmission to compensate for prolonged, excessive changes in neuronal activity. Both excitatory and inhibitory neurons undergo homeostatic changes based on synaptic transmission strength, which could effectively contribute to a fine-tuning of circuit activity. However, gene regulation that underlies homeostatic synaptic plasticity in GABAergic (GABA, gamma aminobutyric) neurons is still poorly understood. The present study demonstrated activity-dependent dynamic scaling in which NMDA-R (N-methyl-D-aspartic acid receptor) activity regulated the expression of GABA synthetic enzymes: glutamic acid decarboxylase 65 and 67 (GAD65 and GAD67). Results revealed that activity-regulated BDNF (brain-derived neurotrophic factor) release is necessary, but not sufficient, for activity-dependent up-scaling of these GAD isoforms. Bidirectional forms of activity-dependent GAD expression require both BDNF-dependent and BDNF-independent pathways, both triggered by NMDA-R activity. Additional results indicated that these two GAD genes differ in their responsiveness to chronic changes in neuronal activity, which could be partially caused by differential dependence on BDNF. In parallel to activity-dependent bidirectional scaling in GAD expression, the present study further observed that a chronic change in neuronal activity leads to an alteration in neurotransmitter release from GABAergic neurons in a homeostatic, bidirectional fashion. Therefore, the differential expression of GAD65 and 67 during prolonged changes in neuronal activity may be implicated in some aspects of bidirectional homeostatic plasticity within mature GABAergic presynapses.

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Related in: MedlinePlus

Different bidirectional forms of activity-dependent gene regulation governing GAD expression.(A) Cultured cortical neurons were treated with 50 μM bicuculline on DIV14 or with 1 μM TTX on DIV12 and were harvested on DIV15. (B) Shows reciprocal effects of bicuculline and TTX on relative expression levels of mRNAs encoding GABAergic and glutamatergic presynaptic proteins in cultured cortical neurons treated as shown in (A). GAD67: F(2, 14) = 106.5 (p < .0001); GAD65: F (2, 14) = 62.36 (p < .0001); vGluT1: F(2, 14) = 11.52 (p = 0.001); VAMP2: F(2, 14) = 1.26 (no significant difference, p = 0.31), one-way ANOVA. (n = 5–6 in each group). GAD: glutamic acid decarboxylase; DIV: days in vitro; TTX: tetrodotoxin.
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pone.0134296.g001: Different bidirectional forms of activity-dependent gene regulation governing GAD expression.(A) Cultured cortical neurons were treated with 50 μM bicuculline on DIV14 or with 1 μM TTX on DIV12 and were harvested on DIV15. (B) Shows reciprocal effects of bicuculline and TTX on relative expression levels of mRNAs encoding GABAergic and glutamatergic presynaptic proteins in cultured cortical neurons treated as shown in (A). GAD67: F(2, 14) = 106.5 (p < .0001); GAD65: F (2, 14) = 62.36 (p < .0001); vGluT1: F(2, 14) = 11.52 (p = 0.001); VAMP2: F(2, 14) = 1.26 (no significant difference, p = 0.31), one-way ANOVA. (n = 5–6 in each group). GAD: glutamic acid decarboxylase; DIV: days in vitro; TTX: tetrodotoxin.

Mentions: To examine GAD gene regulation details during chronic neuronal activity changes, we first checked the level of GAD mRNAs in cultured cortical neurons treated with bicuculline and tetrodotoxin (TTX). This was done along with vesicular presynaptic protein levels regulated by neuronal activity, as reported previously [21] (Fig 1A). Our qPCR analyses revealed that mRNA levels of the two GAD isoforms were significantly increased in bicuculline-treated cultures compared to untreated ones (GAD65 1.9 ± 0.1 fold, p < .001; GAD67, 1.36 ± 0.09 fold, p < .01) and significantly decreased in TTX-treated cultures (GAD65 0.66 ± 0.03 fold, p < .001; GAD67, 0.40 ± 0.04 fold, p < .001) (Fig 1B). Thus, both GADs showed a bidirectional form of activity-dependent change. In parallel, we also observed significant activity-dependent change in the mRNA levels of vesicular GABA transporter (vGAT) and vesicular glutamate transporter 1 (vGluT1), as reported previously [21]. However, this alteration was partial or smaller than that of the two GAD isoforms. Synaptobrevin (VAMP2) mRNA level was not significantly altered.


Activity-Dependent Bidirectional Regulation of GAD Expression in a Homeostatic Fashion Is Mediated by BDNF-Dependent and Independent Pathways.

Hanno-Iijima Y, Tanaka M, Iijima T - PLoS ONE (2015)

Different bidirectional forms of activity-dependent gene regulation governing GAD expression.(A) Cultured cortical neurons were treated with 50 μM bicuculline on DIV14 or with 1 μM TTX on DIV12 and were harvested on DIV15. (B) Shows reciprocal effects of bicuculline and TTX on relative expression levels of mRNAs encoding GABAergic and glutamatergic presynaptic proteins in cultured cortical neurons treated as shown in (A). GAD67: F(2, 14) = 106.5 (p < .0001); GAD65: F (2, 14) = 62.36 (p < .0001); vGluT1: F(2, 14) = 11.52 (p = 0.001); VAMP2: F(2, 14) = 1.26 (no significant difference, p = 0.31), one-way ANOVA. (n = 5–6 in each group). GAD: glutamic acid decarboxylase; DIV: days in vitro; TTX: tetrodotoxin.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4524701&req=5

pone.0134296.g001: Different bidirectional forms of activity-dependent gene regulation governing GAD expression.(A) Cultured cortical neurons were treated with 50 μM bicuculline on DIV14 or with 1 μM TTX on DIV12 and were harvested on DIV15. (B) Shows reciprocal effects of bicuculline and TTX on relative expression levels of mRNAs encoding GABAergic and glutamatergic presynaptic proteins in cultured cortical neurons treated as shown in (A). GAD67: F(2, 14) = 106.5 (p < .0001); GAD65: F (2, 14) = 62.36 (p < .0001); vGluT1: F(2, 14) = 11.52 (p = 0.001); VAMP2: F(2, 14) = 1.26 (no significant difference, p = 0.31), one-way ANOVA. (n = 5–6 in each group). GAD: glutamic acid decarboxylase; DIV: days in vitro; TTX: tetrodotoxin.
Mentions: To examine GAD gene regulation details during chronic neuronal activity changes, we first checked the level of GAD mRNAs in cultured cortical neurons treated with bicuculline and tetrodotoxin (TTX). This was done along with vesicular presynaptic protein levels regulated by neuronal activity, as reported previously [21] (Fig 1A). Our qPCR analyses revealed that mRNA levels of the two GAD isoforms were significantly increased in bicuculline-treated cultures compared to untreated ones (GAD65 1.9 ± 0.1 fold, p < .001; GAD67, 1.36 ± 0.09 fold, p < .01) and significantly decreased in TTX-treated cultures (GAD65 0.66 ± 0.03 fold, p < .001; GAD67, 0.40 ± 0.04 fold, p < .001) (Fig 1B). Thus, both GADs showed a bidirectional form of activity-dependent change. In parallel, we also observed significant activity-dependent change in the mRNA levels of vesicular GABA transporter (vGAT) and vesicular glutamate transporter 1 (vGluT1), as reported previously [21]. However, this alteration was partial or smaller than that of the two GAD isoforms. Synaptobrevin (VAMP2) mRNA level was not significantly altered.

Bottom Line: Additional results indicated that these two GAD genes differ in their responsiveness to chronic changes in neuronal activity, which could be partially caused by differential dependence on BDNF.In parallel to activity-dependent bidirectional scaling in GAD expression, the present study further observed that a chronic change in neuronal activity leads to an alteration in neurotransmitter release from GABAergic neurons in a homeostatic, bidirectional fashion.Therefore, the differential expression of GAD65 and 67 during prolonged changes in neuronal activity may be implicated in some aspects of bidirectional homeostatic plasticity within mature GABAergic presynapses.

View Article: PubMed Central - PubMed

Affiliation: Tokai University Institute of Innovative Science and Technology, Medical Division, Kanagawa, Japan; School of Medicine, Tokai University, Kanagawa, Japan.

ABSTRACT
Homeostatic synaptic plasticity, or synaptic scaling, is a mechanism that tunes neuronal transmission to compensate for prolonged, excessive changes in neuronal activity. Both excitatory and inhibitory neurons undergo homeostatic changes based on synaptic transmission strength, which could effectively contribute to a fine-tuning of circuit activity. However, gene regulation that underlies homeostatic synaptic plasticity in GABAergic (GABA, gamma aminobutyric) neurons is still poorly understood. The present study demonstrated activity-dependent dynamic scaling in which NMDA-R (N-methyl-D-aspartic acid receptor) activity regulated the expression of GABA synthetic enzymes: glutamic acid decarboxylase 65 and 67 (GAD65 and GAD67). Results revealed that activity-regulated BDNF (brain-derived neurotrophic factor) release is necessary, but not sufficient, for activity-dependent up-scaling of these GAD isoforms. Bidirectional forms of activity-dependent GAD expression require both BDNF-dependent and BDNF-independent pathways, both triggered by NMDA-R activity. Additional results indicated that these two GAD genes differ in their responsiveness to chronic changes in neuronal activity, which could be partially caused by differential dependence on BDNF. In parallel to activity-dependent bidirectional scaling in GAD expression, the present study further observed that a chronic change in neuronal activity leads to an alteration in neurotransmitter release from GABAergic neurons in a homeostatic, bidirectional fashion. Therefore, the differential expression of GAD65 and 67 during prolonged changes in neuronal activity may be implicated in some aspects of bidirectional homeostatic plasticity within mature GABAergic presynapses.

No MeSH data available.


Related in: MedlinePlus