Modulation of extrasynaptic GABAA alpha 5 receptors in the ventral hippocampus normalizes physiological and behavioral deficits in a circuit specific manner

Donegan, Jennifer J.; Boley, Angela M.; Yamaguchi, Junya; Toney, Glenn M.; Lodge, Daniel J.

doi:10.1038/s41467-019-10800-1

Cited by 50 publications

(86 citation statements)

References 67 publications

(99 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4e ). We have also selected α5-containing GABA A Rs (α5β2γ2) as a representative for an extrasynaptic GABA A R 29 , 30 , and examined the effect of GABARAP on this type of GABA A R. GABARAP also significantly increased the GABA A R-mediated current as induced by 1 mM GABA (Supplementary Fig. 5a ), suggesting that γ2 containing extrasynaptic GABA A Rs are also sensitive to regulation by GABARAP.…”

Section: Resultsmentioning

confidence: 99%

Structural basis of GABARAP-mediated GABAA receptor trafficking and functions on GABAergic synaptic transmission

Zou

Zhu

et al. 2021

Nat Commun

View full text Add to dashboard Cite

GABAA receptors (GABAARs) are the primary fast inhibitory ion channels in the central nervous system. Dysfunction of trafficking and localization of GABAARs to cell membranes is clinically associated with severe psychiatric disorders in humans. The GABARAP protein is known to support the stability of GABAARs in synapses, but the underlying molecular mechanisms remain to be elucidated. Here, we show that GABARAP/GABARAPL1 directly binds to a previously unappreciated region in the γ2 subunit of GABAAR. We demonstrate that GABARAP functions to stabilize GABAARs via promoting its trafficking pathway instead of blocking receptor endocytosis. The GABARAPL1–γ2-GABAAR crystal structure reveals the mechanisms underlying the complex formation. We provide evidence showing that phosphorylation of γ2-GABAAR differentially modulate the receptor’s binding to GABARAP and the clathrin adaptor protein AP2. Finally, we demonstrate that GABAergic synaptic currents are reduced upon specific blockage of the GABARAP–GABAAR complex formation. Collectively, our results reveal that GABARAP/GABARAPL1, but not other members of the Atg8 family proteins, specifically regulates synaptic localization of GABAARs via modulating the trafficking of the receptor.

show abstract

Section: Resultsmentioning

confidence: 99%

Structural basis of GABARAP-mediated GABAA receptor trafficking and functions on GABAergic synaptic transmission

Zou

Zhu

et al. 2021

Nat Commun

View full text Add to dashboard Cite

show abstract

“…Previous studies have shown the involvement of a5 subunits in tonic inhibitory currents recorded in the hippocampus and neocortex (Caraiscos et al, 2004;Jacob, 2019). Pharmacological or genetic manipulation of a5 activity can produce significant modulation of learning and cognitive ability (Braudeau et al, 2011;Collinson et al, 2002;Donegan et al, 2019;Magnin et al, 2019). Altered a5 expression has also been linked to neuropsychiatric disorders, and a5 modulators may have antidepressant actions (Carreno et al, 2020;Prevot et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Tonic GABAergic activity facilitates dendritic calcium signaling and short-term plasticity

Chiu

Morse²,

Nani

et al. 2020

Preprint

View full text Add to dashboard Cite

These authors contributed equally to this work. Summary:Brain activity is highly regulated by GABAergic activity, which acts via GABAARs to suppress somatic spike generation as well as dendritic synaptic integration and calcium signaling. Tonic GABAergic conductances mediated by distinct receptor subtypes can also inhibit neuronal excitability and spike output, though the consequences for dendritic calcium signaling are unclear. Here, we use 2-photon calcium imaging in cortical pyramidal neurons and computational modeling to show that low affinity GABAARs containing an a5 subunit mediate a tonic hyperpolarization of the dendritic membrane potential, resulting in deinactivation of voltage-gated calcium channels and a paradoxical boosting of action potential-evoked calcium influx. We also find that GABAergic enhancement of calcium signaling modulates short-term synaptic plasticity, augmenting depolarization-induced suppression of inhibition. These results demonstrate a novel role for GABA in the control of dendritic activity and suggest a mechanism for differential modulation of electrical and biochemical signaling. comments during the preparation of this manuscript, the Yale Center for Research Computing for support with the Yale Farnam high performance cluster, Henner Knust for compound synthesis, Chiristian Miscenic and Marcello Foggetta for cell transfections and membrane preparations, Judith Lengyel, Gregoire Friz, and Maria Karg for cell line generation and radioligand binding assays, and Marie Claire Pflimlin for support with electrophysiological characterization of Compound A selectivity.

show abstract

“…Whilst this supports a link between α5-GABA A Rs dysregulation and the clinical expression of the disorder, the direction of the association is not consistent with a simple model of α5-GABA A Rs hypofunction leading to hippocampal overactivity and symptoms. It was recently shown, using a viral-mediated gene transfer, that an increase in the expression of α5-GABA A Rs normalizes VTA dopamine cell population activity [71]. Thus, one explanation that could account for both the lower [11C] Ro15-4513 binding in patients and a positive correlation with symptoms is that low α5-GABA A R levels are a vulnerability factor but that once the disorder develops there is a compensatory increase in α5-GABA A R levels in response to dysregulation of other systems.…”

Section: Strengths and Limitationsmentioning

confidence: 99%

GABA-A receptor differences in schizophrenia: a positron emission tomography study using [11C]Ro154513

et al. 2020

View full text Add to dashboard Cite

A loss of GABA signaling is a prevailing hypothesis for the pathogenesis of schizophrenia. Preclinical studies indicate that blockade of the α5 subtype of the GABA receptor (α5-GABA A Rs) leads to behavioral phenotypes associated with schizophrenia, and postmortem evidence indicates lower hippocampal α5-GABA A Rs protein and mRNA levels in schizophrenia. However, it is unclear if α5-GABA A Rs are altered in vivo or related to symptoms. We investigated α5-GABA A Rs availability in antipsychotic-free schizophrenia patients and antipsychotic-medicated schizophrenia patients using [ 11 C]Ro15-4513 PET imaging in a cross-sectional, case-control study design. Thirty-one schizophrenia patients (n = 10 antipsychotic free) and twenty-nine matched healthy controls underwent a [ 11 C]Ro15-4513 PET scan and MRI. The α5 subtype GABA-A receptor availability was indexed using [ 11 C]Ro15-4513 PET imaging. Dynamic PET data were analyzed using the two-tissue compartment model with an arterial plasma input function and total volume of distribution (V T ) as the outcome measure. Symptom severity was assessed using the PANSS scale. There was significantly lower [11C] Ro15-4513 V T in the hippocampus of antipsychotic-free patients, but not in medicated patients (p = 0.64), relative to healthy controls (p < 0.05; effect size = 1.4). There was also a significant positive correlation between [ 11 C]Ro15-4513 V T and total PANSS score in antipsychotic-free patients (r = 0.72; p = 0.044). The results suggest that antipsychotic-free patients with schizophrenia have lower α5-GABAARs levels in the hippocampus, consistent with the hypothesis that GABA hypofunction underlies the pathophysiology of the disorder.

show abstract

Modulation of extrasynaptic GABAA alpha 5 receptors in the ventral hippocampus normalizes physiological and behavioral deficits in a circuit specific manner

Cited by 50 publications

References 67 publications

Structural basis of GABARAP-mediated GABAA receptor trafficking and functions on GABAergic synaptic transmission

Structural basis of GABARAP-mediated GABAA receptor trafficking and functions on GABAergic synaptic transmission

Tonic GABAergic activity facilitates dendritic calcium signaling and short-term plasticity

GABA-A receptor differences in schizophrenia: a positron emission tomography study using [11C]Ro154513

Contact Info

Product

Resources

About