Microglial VRK2 Regulates Astrocytic GABA Synthesis and Tonic Inhibition in the Thalamus

TL;DR

The study shows that VRK2 in microglia controls GABA production in astrocytes in the thalamus, affecting brain inhibition and possibly contributing to neurodevelopmental disorders.

Contribution

The paper identifies a novel microglia-astrocyte signaling pathway involving VRK2 and TNF-α that regulates thalamic inhibition.

Findings

VRK2 deletion in mice reduces tonic GABA currents in the mediodorsal thalamus.

Microglial VRK2 regulates astrocytic GABA synthesis via TNF-α signaling.

DAO–ALDH1A1 pathway in astrocytes is downregulated in VRK2-deficient mice.

Abstract

Vaccinia‐related kinase 2 (VRK2) is a prominent genetic risk factor for neurodevelopmental disorders (NDDs), including schizophrenia and epilepsy, which are characterized by cognitive and behavioral impairments. The mediodorsal (MD) thalamus, a higher‐order nucleus involved in executive function and social behavior, is frequently disrupted in these conditions. However, how VRK2 influences thalamic regulation remains unclear. Here, we show that Vrk2‐deficient mice exhibit a significant reduction in tonic GABA currents in the MD thalamus, accompanied by decreased excitatory synaptic input but preserved intrinsic neuronal excitability. Although VRK2 is not expressed in astrocytes, its deletion impaired astrocyte‐mediated tonic inhibition, suggesting a non‐cell‐autonomous mechanism. Single‐cell and bulk transcriptomic analyses revealed that VRK2 is specifically expressed in microglia and that its loss alters cytokine signaling pathways. Pharmacological depletion of microglia or TNF‐α inhibition in wild‐type mice recapitulated the tonic inhibition deficits observed in Vrk2‐deficient animals. Further, astrocyte‐specific interventions revealed that tonic GABA is synthesized through the DAO–ALDH1A1 pathway, which was selectively downregulated in the absence of VRK2, while MAOB, BEST1, and GABA receptor components remained unchanged. These findings define a novel glial–glial signaling axis in which microglial VRK2 maintains thalamic inhibitory tone through cytokine‐dependent regulation of astrocytic GABA synthesis. This mechanism operates across both first‐ and higher‐order thalamic nuclei and may underlie sensory and cognitive impairments associated with VRK2‐linked NDDs. Our work provides new insight into glial coordination as a critical regulator of tonic inhibition and highlights microglial cytokine signaling as a molecular bridge between genetic risk and circuit‐level dysfunction.

In Vrk2‐deficient mice, tonic GABA inhibition is reduced in the mediodorsal thalamus due to impaired astrocytic GABA synthesis.Microglial VRK2 regulates this process via TNF‐α signaling, revealing a glial–glial mechanism of thalamic inhibition.

In Vrk2‐deficient mice, tonic GABA inhibition is reduced in the mediodorsal thalamus due to impaired astrocytic GABA synthesis.

Microglial VRK2 regulates this process via TNF‐α signaling, revealing a glial–glial mechanism of thalamic inhibition.

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