Intra-accumbens infusions of antisense oligodeoxynucleotides to one isoform of glutamic acid decarboxylase mRNA, GAD65, but not to GAD67 mRNA, impairs sustained attention performance in the rat

Miner, Lee Ann H.; Sarter, Martin

doi:10.1016/s0926-6410(98)00030-5

Cited by 15 publications

(10 citation statements)

References 80 publications

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“…In contrast, IL inactivation has no effect on fear expression but does impair within-session extinction learning and extinction memory (Sierra-Mercado et al 2011). Neurons expressing high levels of GAD67 may provide tonic inhibition (Miner and Sarter 1999). The increase in Gad67 expression we observed in IL may thus represent an increase in basal activity of GABA neurons and increased inhibition of the PL by the IL.…”

Section: Possible Role Of Increased Gad67 Expression In the Infralimbmentioning

confidence: 70%

“…Furthermore, there are reciprocal interactions between types of GABAergic neurons within the lateral division, which result in both inhibitory and disinhibitory influences on the output neurons of the medial division and thereby contribute to fear acquisition and generalization (Ciocchi et al 2010). Because GAD65 is generally found in apoenzyme form, it may serve as a reserve supply of inactive enzyme that can become activated in response to increased demands on GABAergic neurons, and therefore GAD65 may be elevated in neurons that are highly sensitive to regulation by afferent input (Miner and Sarter 1999). An increase in GAD65-mediated GABAergic signaling in the CE might indicate a functional reorganization of these intricate circuits, leading to reduced amygdalar output and fear expression.…”

Section: Possible Role Of Increased Gad65 Expression In the Central Amentioning

confidence: 99%

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Differential regulation of glutamic acid decarboxylase gene expression after extinction of a recent memory vs. intermediate memory

Sangha

Ilenseer²,

Sosulina³

et al. 2012

Learn. Mem.

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Extinction reduces fear to stimuli that were once associated with an aversive event by no longer coupling the stimulus with the aversive event. Extinction learning is supported by a network comprising the amygdala, hippocampus, and prefrontal cortex. Previous studies implicate a critical role of GABA in extinction learning, specifically the GAD65 isoform of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD). However, a detailed analysis of changes in gene expression of GAD in the subregions comprising the extinction network has not been undertaken. Here, we report changes in gene expression of the GAD65 and GAD67 isoforms of GAD, as measured by relative quantitative real-time RT-PCR, in subregions of the amygdala, hippocampus, and prefrontal cortex 24 -26 h after extinction of a recent (1-d) or intermediate (14-d) fear memory. Our results show that extinction of a recent memory induces a down-regulation of Gad65 gene expression in the hippocampus (CA1, dentate gyrus) and an up-regulation of Gad67 gene expression in the infralimbic cortex. Extinguishing an intermediate memory increased Gad65 gene expression in the central amygdala. These results indicate a differential regulation of Gad gene expression after extinction of a recent memory vs. intermediate memory.

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Section: Possible Role Of Increased Gad67 Expression In the Infralimbmentioning

confidence: 70%

Section: Possible Role Of Increased Gad65 Expression In the Central Amentioning

confidence: 99%

Differential regulation of glutamic acid decarboxylase gene expression after extinction of a recent memory vs. intermediate memory

Sangha

Ilenseer²,

Sosulina³

et al. 2012

Learn. Mem.

View full text Add to dashboard Cite

show abstract

“…The inhibition of dopamine transmission is also under the control of descending GABAergic projections from the nucleus accumbens to subpallidal regions, including the ventral pallidum (Koch and Schnitzler, 1997). Experiments using in vivo injections of GAD65 isoform-specific antisense oligonucleotides into nucleus accumbens have further demonstrated the requirement of GAD65 in attentional processes (Miner and Sarter, 1999). Thus, a reduction of GAD65-dependent GABA activity would be expected to lead to hyperactivity of midbrain and forebrain dopamine neurons.…”

Section: Discussionmentioning

confidence: 99%

Prepulse Inhibition Deficits in GAD65 Knockout Mice and the Effect of Antipsychotic Treatment

Heldt

Green

Ressler

2004

Neuropsychopharmacol

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Recent postmortem studies in humans suggest that defects in GABAergic neurotransmission might contribute to the neuropathology associated with schizophrenia. Disturbances in GABAergic systems may also contribute to the sensorimotor gating deficits classically observed in schizophrenic patients, including deficits in prepulse inhibition (PPI). To explore the relationship, the current study examined the integrity of PPI and startle habituation in knockout (KO) mice that lack the GABA synthesizing enzyme glutamic acid decarboxylase 65 (GAD 65). GAD65 KO mice displayed normal baseline and habituated startle responses, which did not differ from GAD65 wild-type (WT) or heterozygous (HET) mice. However, GAD65 KO mice showed robust deficits in PPI which were reversed by the atypical antipsychotic agent clozapine. These results lend support to the view that abnormalities in GABAergic systems might contribute to the basic pathophysiological mechanisms in schizophrenia.

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“…Oligodeoxynucleotides were phosphorothioated on the three terminal bases of both 5’ and 3’ ends to increase stability and minimize nonspecific toxicity. Oligodeoxynucleotide sequences and concentrations were derived from previous studies 33, 34: glutamate decarboxylase 67 (GAD 67 ) antisense oligonucleotide (ASO), glutamate decarboxylase 65 (GAD 65 ) antisense, scrambled sequence control for GAD 67 , and scrambled sequence control for GAD 65 .…”

Section: Methodsmentioning

confidence: 99%

Gamma Aminobutyric Acidergic and Neuronal Structural Markers in the Nucleus Accumbens Core Underlie Trait-like Impulsive Behavior

Caprioli

Sawiak

Merlo

et al. 2014

Biological Psychiatry

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BackgroundPathological forms of impulsivity are manifest in a number of psychiatric disorders listed in DSM-5, including attention-deficit/hyperactivity disorder and substance use disorder. However, the molecular and cellular substrates of impulsivity are poorly understood. Here, we investigated a specific form of motor impulsivity in rats, namely premature responding, on a five-choice serial reaction time task.MethodsWe used in vivo voxel-based magnetic resonance imaging and ex vivo Western blot analyses to investigate putative structural, neuronal, and glial protein markers in low-impulsive (LI) and high-impulsive rats. We also investigated whether messenger RNA interference targeting glutamate decarboxylase 65/67 (GAD65/67) gene expression in the nucleus accumbens core (NAcbC) is sufficient to increase impulsivity in LI rats.ResultsWe identified structural and molecular abnormalities in the NAcbC associated with motor impulsivity in rats. We report a reduction in gray matter density in the left NAcbC of high-impulsive rats, with corresponding reductions in this region of glutamate decarboxylase (GAD65/67) and markers of dendritic spines and microtubules. We further demonstrate that the experimental reduction of de novo of GAD65/67 expression bilaterally in the NAcbC is sufficient to increase impulsivity in LI rats.ConclusionsThese results reveal a novel mechanism of impulsivity in rats involving gamma aminobutyric acidergic and structural abnormalities in the NAcbC with potential relevance to the etiology and treatment of attention-deficit/hyperactivity disorder and related disorders.

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Intra-accumbens infusions of antisense oligodeoxynucleotides to one isoform of glutamic acid decarboxylase mRNA, GAD65, but not to GAD67 mRNA, impairs sustained attention performance in the rat

Cited by 15 publications

References 80 publications

Differential regulation of glutamic acid decarboxylase gene expression after extinction of a recent memory vs. intermediate memory

Differential regulation of glutamic acid decarboxylase gene expression after extinction of a recent memory vs. intermediate memory

Prepulse Inhibition Deficits in GAD65 Knockout Mice and the Effect of Antipsychotic Treatment

Gamma Aminobutyric Acidergic and Neuronal Structural Markers in the Nucleus Accumbens Core Underlie Trait-like Impulsive Behavior

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