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

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.