Histone Deacetylase Inhibition Restores Behavioral and Synaptic Function in a Mouse Model of 16p11.2 Deletion

Microdeletion of the human 16p11.2 gene locus confers risk for autism spectrum disorders and intellectual disability. How 16p11.2 deletion is linked to these neurodevelopmental disorders and whether there are treatment avenues for the manifested phenotypes remain to be elucidated. Emerging evidence suggests that epigenetic aberrations are strongly implicated in autism.

We performed behavioral and electrophysiological experiments to examine the therapeutic effects of epigenetic drugs in transgenic mice carrying 16p11.2 deletion (16p11del/+).

We found that 16p11del/+ mice exhibited a significantly reduced level of histone acetylation in the prefrontal cortex (PFC). A short (3-day) treatment with class I histone deacetylase (HDAC) inhibitor MS-275 or Romidepsin led to the prolonged (3-4 weeks) rescue of social and cognitive deficits in 16p11del/+ mice. Concomitantly, MS-275 treatment reversed the hypoactivity of PFC pyramidal neurons and the hyperactivity of PFC fast-spiking interneurons. Moreover, the diminished N-methyl-D-aspartate (NMDA) receptor-mediated synaptic currents and the elevated GABAA receptor-mediated synaptic currents in PFC pyramidal neurons of 16p11del/+ mice were restored to control levels by MS-275 treatment.

Our results suggest that HDAC inhibition provides a highly effective therapeutic strategy for behavioral deficits and excitation/inhibition imbalance in 16p11del/+ mice, likely via normalization of synaptic function in the PFC.