Embryonic loss of hexokinase 2 promotes cortical progenitor proliferation and causes autism-like behaviors in mice

Neurodevelopmental disorders are increasingly associated with metabolic abnormalities, but how metabolic pathways regulate cortical development remains unclear. In particular, whether glycolytic enzymes control neural progenitor behavior during embryonic corticogenesis is still poorly understood. Here, we first found that HK2 was highly expressed in the early embryonic mouse cortex and selectively enriched in cortical neural progenitor cells (NPCs), with expression progressively declining as development proceeded. Based on this expression pattern, we generated a neural progenitor-specific conditional knockout mouse model ( Hk2 -cKO) and found that loss of HK2 at embryonic day 12 (E12) unexpectedly enhanced cortical NPC proliferation in vivo and increased the production of deep-layer projection neurons, including CTIP2-positive and TBR1-positive neurons. Furthermore, HK2 deficiency altered cell-cycle distribution, as reflected by reduced G 0 /G 1 -phase cells and increased S- and G 2 /M-phase cells. Mechanistically, HK2 deficiency led to reduced expression of TXNIP and enhanced AKT signaling in both embryonic forebrain tissue and cultured neurospheres. Importantly, Hk2 -cKO adult male mice displayed core autism-like behavioral abnormalities, including impaired social interaction and increased repetitive behaviors, while locomotor activity, anxiety-like behavior, and spatial learning and memory were largely unaffected. Together, these findings identify HK2 as an important metabolic regulator associated with embryonic cortical progenitor homeostasis and suggest that early metabolic disruption can contribute to autism-related phenotypes.