Microglial TREM2 deficiency causes E/I imbalance and triggers ASD-like behaviors by altering potassium channel Kv1.3 activation.

Scientists studied mice with changes in brain immune cells called microglia to understand autism. When a protein called TREM2 was missing, it caused brain activity to become unbalanced - too much excitement and not enough calming signals. This led to autism-like behaviors in the mice. When researchers blocked a specific channel (Kv1.3) that was overactive, the brain balance improved and autism-like behaviors reduced. This suggests new potential treatment approaches.

This mouse model study investigated how microglial TREM2 deficiency contributes to autism-like behaviors. Researchers found that loss of TREM2 in microglia during early development increased activity of Kv1.3 potassium channels, leading to excitatory/inhibitory (E/I) imbalance in brain circuits and neuronal hyperactivity in the cortex. TREM2-deficient mice displayed autism-like behaviors. Importantly, both genetic knockout and pharmacological inhibition of Kv1.3 channels restored normal E/I balance, reduced neuronal hyperactivity, and improved behavioral symptoms.

The findings suggest Kv1.3 channels as a potential therapeutic target, providing mechanistic insight into how microglial dysfunction may contribute to autism pathophysiology through synaptic transmission alterations.

Identifies Kv1.3 channels as potential therapeutic targets for autism treatment. Supports E/I imbalance theory and highlights role of microglial dysfunction in autism pathophysiology. However, translation from mouse models to human therapies requires extensive additional research including safety studies and clinical trials.

Single mouse model study with unclear sample sizes. Findings may not translate to human autism given species differences. Limited to one genetic pathway (TREM2 deficiency). No long-term safety or efficacy data for Kv1.3 inhibition approaches.

Autism Spectrum Disorder (ASD) is a type of neurodevelopmental disorder characterized by deficits in social interaction and stereotyped behavior, with synaptic dysfunction playing a causal role in its pathogenesis. Microglia, as innate immune cells in CNS, are involved in regulation of synaptic transmission and plasticity through directly pruning spines and indirectly releasing bioactive substances. Interestingly, loss-of-function of triggering receptor expressed on myeloid cells 2 (TREM2), a key receptor in regulation of microglial immune functions, has been implicated in neurodevelopmental and neurodegenerative diseases through altering synaptic transmission and neuronal homeostasis. However, it is currently still not well established how TREM2 loss-of-function causes those effects.

Here, we found that TREM2 deficiency during early postnatal stage led to an increased Kv1.3 channel activity in microglia, which resulted in an imbalance of excitatory and inhibitory synaptic transmissions (E/I imbalance) characterized by increased mEPSCs and reduced mIPSCs frequencies, leading to neuronal hyperactivity in neocortex. Importantly, Kv1.3 conditional knock-out and specific pharmacological inhibition effectively restored the E/I imbalance and neuronal hyperactivity, and alleviated ASD-like behaviors in TREM2-deficient mice. Together, our findings suggest that the increased Kv1.3 activity may underlie the neuronal dysfunction and behavioral deficits associated with TREM-2 deficiency, highlighting Kv1.3 as a potential therapeutic target for ASD treatment.