Genetic mapping identifies Homer1 as a developmental modifier of attention

Attention is the process of directing cognitive resources toward specific stimuli and is required for most higher-order cognitive functions. The genetic factors and resulting neural circuit physiology that drive variation in this trait are not well understood. Here we took an unbiased forward genetics approach to identify genes of large effect on attention. We performed genetic mapping on 200 genetically diverse mice and identified a small locus on chromosome 13 that is significantly associated with pre-attentive processing. Further characterization of the locus revealed Homer1, encoding a synaptic protein, as a potential driver gene that merited further investigation. Strikingly, down-regulation of specifically the short isoforms of Homer1 in prefrontal cortex (PFC) during an early developmental window led to improvements in multiple measures of attention in the adult. An important functional consequence of low Homer1 is a resulting upscaling of GABAergic receptors and enhanced inhibitory tone in PFC. These Homer1-dependent changes to inhibitory tone led to overall improvements in neural signal-to-noise, cue detection, and fast latency correct choices. We thus identify a single locus of large effect on attention and propose Homer1-dependent inhibitory tone, sculpted during a developmental sensitive period, as a key regulator of adult attentional performance.