Neural mechanisms contributing to increased acoustic startle reactivity in Cntnap2 knock-out rats.

Rats with a loss-of-function mutation in the contactin-associated protein-like 2 (Cntnap2) gene exhibit increased acoustic startle response magnitudes, paralleling the acoustic hyperreactivity that is observed in CNTNAP2-associated disorders in humans, including autism spectrum disorder. Previous studies have found increased neural activity in the brainstem region that mediates the acoustic startle response, the caudal pontine reticular nucleus (PnC). This increased neural activity was predominantly caused by increased PnC firing rates in female Cntnap2 KO rats, whereas in male Cntnap2 KO rats an increased number of PnC giant neurons were recruited in response to startle sounds. However, the mechanisms underlying this increased PnC activity in Cntnap2 KO rats are currently unknown. We thus investigated potential factors that could contribute to increased PnC activity: we analyzed the expression of glutamate receptor subunits Gria1 and Gria4 in PnC giant neurons, given the glutamatergic nature of auditory inputs into the PnC. Additionally, we investigated the activation of cochlear root neurons (CRNs), the major input neurons to the PnC within the acoustic startle circuit. We found no differences in Gria1 or Gria4 mRNA levels in PnC giant neurons of Cntnap2 KO rats, but increased CRN activation after exposure to startle sounds in KO rats. These findings indicate that at least some of the changes leading to Cntnap2-/--associated hyperreactivity occur in the cochlear nucleus and/or the cochlear nerve root.