Extrasynaptic GABAA receptors in mediodorsal thalamic nucleus modulate fear extinction learning

Paydar, Afshin; Lee, Bo Yong; Gangadharan, Gireesh; Lee, Sukchan; Hwang, Eun Mi; Shin, Hee Sup

doi:10.1186/1756-6606-7-39

Cited by 22 publications

(16 citation statements)

References 36 publications

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“…The Gabra3-selective benzodiazepine site agonist and anxiolytic compound TP003 increased tonic currents and markedly dampen excitability in BLA principal cells 56 . Gabra4 was involved in fear extinction learning, and knockout of the extrasynaptic GABA A Rs facilitated fear extinction 57 . Altered expression also included Nsf , which was shown to downregulate GABA A Rs with PKCε 58 .…”

Section: Discussionmentioning

confidence: 99%

Ulk4 regulates GABAergic signaling and anxiety-related behavior

et al. 2018

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Excitation/inhibition imbalance has been proposed as a fundamental mechanism in the pathogenesis of neuropsychiatric and neurodevelopmental disorders, in which copy number variations of the Unc-51 like kinase 4 (ULK4) gene encoding a putative Serine/Threonine kinase have been reported in approximately 1/1000 of patients suffering pleiotropic clinical conditions of schizophrenia, depression, autistic spectrum disorder (ASD), developmental delay, language delay, intellectual disability, or behavioral disorder. The current study characterized behavior of heterozygous Ulk4+/tm1a mice, demonstrating that Ulk4+/tm1a mice displayed no schizophrenia-like behavior in acoustic startle reactivity and prepulse inhibition tests or depressive-like behavior in the Porsolt swim or tail suspension tests. However, Ulk4+/tm1a mice exhibited an anxiety-like behavioral phenotype in several tests. Previously identified hypo-anxious (Atp1a2, Ptn, and Mdk) and hyper-anxious (Gria1, Syngap1, and Npy2r) genes were found to be dysregulated accordingly in Ulk4 mutants. Ulk4 was found to be expressed in GABAergic neurons and the Gad67+ interneurons were significantly reduced in the hippocampus and basolateral amygdala of Ulk4+/tm1a mice. Transcriptome analyses revealed a marked reduction of GABAergic neuronal subtypes, including Pvalb, Sst, Cck, Npy, and Nos3, as well as significant upregulation of GABA receptors, including Gabra1, Gabra3, Gabra4, Gabra5, and Gabrb3. This is the first evidence that Ulk4 plays a major role in regulating GABAergic signaling and anxiety-like behavior, which may have implications for the development of novel anxiolytic treatments.

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Section: Discussionmentioning

confidence: 99%

Ulk4 regulates GABAergic signaling and anxiety-related behavior

et al. 2018

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“…Although many different GABAA receptor isoforms might exist, the major adult brain isoform consists of α 1, β 2, and γ 2 subunits [ 180 ]. GABAA receptors are involved in various kinds of behavioral regulation, including sexual behavior [ 181 ], anxiety [ 182 , 183 ], fear extinction learning [ 184 ], and object recognition memory [ 185 ]. These receptors also represent important pharmacological targets for treatment of several disorders, including epilepsy, anxiety, and alcoholism [ 186 ].…”

Section: Palmitoylation Of Ligand-gated Ion Channels (Lics)mentioning

confidence: 99%

Palmitoylation as a Functional Regulator of Neurotransmitter Receptors

Науменко

Ponimaskin

2018

Neural Plasticity

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The majority of neuronal proteins involved in cellular signaling undergo different posttranslational modifications significantly affecting their functions. One of these modifications is a covalent attachment of a 16-C palmitic acid to one or more cysteine residues (S-palmitoylation) within the target protein. Palmitoylation is a reversible modification, and repeated cycles of palmitoylation/depalmitoylation might be critically involved in the regulation of multiple signaling processes. Palmitoylation also represents a common posttranslational modification of the neurotransmitter receptors, including G protein-coupled receptors (GPCRs) and ligand-gated ion channels (LICs). From the functional point of view, palmitoylation affects a wide span of neurotransmitter receptors activities including their trafficking, sorting, stability, residence lifetime at the cell surface, endocytosis, recycling, and synaptic clustering. This review summarizes the current knowledge on the palmitoylation of neurotransmitter receptors and its role in the regulation of receptors functions as well as in the control of different kinds of physiological and pathological behavior.

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“…The efficacy of topiramate in treating hyperarousal (and possibly reexperiencing) symptoms is supported by its multiple putative mechanistic properties, including enhancement of GABAergic neurotransmission, inhibition of excessive glutamate activity (both via effects on ionotropic receptors and second‐messenger pathways), and blockade of calcium and voltage‐sensitive sodium channels (Guerrini & Parmeggiani, ; Mao et al., ). These effects may contribute to suppression of fear signaling and an increase in the threshold for startle response, nightmares, and flashbacks (Berlant, ; Berlant & van Kammen, ; Paydar et al., ).…”

Section: Discussionmentioning

confidence: 99%

“…Although RCTs that have evaluated the efficacy of augmentation with anticonvulsant medication on individuals with PTSD have had mixed results (Wang, Woo, & Bahk, ), there is emerging evidence that treatment with topiramate, an anticonvulsant medication that enhances the inhibitory activity of ᵞ‐aminobutyric acid (GABA), may in fact be efficacious. Mechanistically, the action of topiramate on GABA receptors may aid in suppressing the fear response, which is overly activated and difficult to modulate in people with PTSD (Berlant, ; Berlant & van Kammen, ; Paydar et al., ).…”

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confidence: 99%

Topiramate as Monotherapy or Adjunctive Treatment for Posttraumatic Stress Disorder: A Meta‐Analysis

Varma

Moore

Miller

et al. 2018

Journal of Traumatic Stress

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Posttraumatic stress disorder (PTSD) is a chronic and debilitating condition for which clinicians sometimes turn to anticonvulsants as a treatment for symptoms. This study was a systematic review and meta-analysis of randomized controlled trials (RCT) that have assessed the efficacy of topiramate as monotherapy or adjunctive therapy, compared to placebo, for the treatment of PTSD in adults. Prescribers may be reluctant to turn to topiramate, given the commonly reported side effects of impaired cognition, sedation, fatigue, and headache. We searched PubMed, PsycInfo, and Cochrane Central databases for relevant trials. Five studies were identified as RCTs and thus met inclusion criteria; one additional nonpublished study was identified via phone contact with its authors. Of these six studies, one was excluded from the statistical meta-analysis due to its high dropout rate (16 of 40 participants). One of these studies was excluded from a stratified analysis of symptom types because this subscale data were unavailable. For overall symptomatology, topiramate showed a medium, but not significant effect, standardized mean difference (SMD) = 0.55, p = .082. Topiramate showed a small and significant reduction of hyperarousal symptoms, SMD = 0.35, 95% CI [0.029, 0.689], p = .033. Topiramate did not significantly reduce reexperiencing symptoms, SMD = 0.29, 95% CI [-0.019, 0.597], p = .067, or avoidance symptoms, SMD = 0.20, 95% CI [-0.105, 0.509], p = .198. Results did not differ significantly between veteran and nonveteran subjects, or between topiramate as monotherapy and adjunctive therapy. Further studies on topiramate will clarify its role in PTSD treatment.

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Extrasynaptic GABAA receptors in mediodorsal thalamic nucleus modulate fear extinction learning

Cited by 22 publications

References 36 publications

Ulk4 regulates GABAergic signaling and anxiety-related behavior

Ulk4 regulates GABAergic signaling and anxiety-related behavior

Palmitoylation as a Functional Regulator of Neurotransmitter Receptors

Topiramate as Monotherapy or Adjunctive Treatment for Posttraumatic Stress Disorder: A Meta‐Analysis

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