The Neural Basis of Altered Acoustic Processing in Cntnap2 Knock-out Rats
Abstract
Rats with a loss-of-function mutation in the contactin-associated protein-like 2 (Cntnap2) gene have increased acoustic startle responses, which parallels acoustic hyperreactivity in CNTNAP2-associated disorders (e.g., in autism spectrum disorder). Although the neural circuit for the acoustic startle response is well-characterized, the neural basis underlying hyperreactivity to sound in CNTNAP2-associated disorders is currently unknown. This thesis investigates various elements along the startle pathway that may contribute to increased acoustic startle in Cntnap2 knock-out rats, with a focus on the caudal pontine reticular nucleus (PnC). In vivo electrophysiological recordings showed that female Cntnap2 knock-out rats have increased multiunit firing rates in the PnC compared with female wildtypes, but male Cntnap2 knock-out rats showed either a modest increase or no difference compared with male wildtypes. This did not fully align with the behavioural findings of both female and male Cntnap2 knock-out rats having significantly increased acoustic startle magnitudes compared with their wildtype counterparts. Therefore, a factor other than PnC firing rates likely contributes to increased startle in male Cntnap2 knock-out rats. Next, immunohistochemical approaches were used to analyze PnC giant neurons, showing that there was increased activation of PnC giant neurons in Cntnap2 knock-out rats after exposure to startle sounds compared with wildtype rats. Additionally, male rats had increased activation of PnC giant neurons compared with female rats. Considering the increased firing rates and increased giant neuron recruitment in the PnC of Cntnap2 knock-out rats, the presynaptic cochlear root neurons (CRNs), the neural substrate upstream of the PnC in the startle circuit, were examined using immunohistochemical approaches. Cntnap2 knock-out rats showed increased activation of CRNs compared with wildtype rats, and CRN activation was correlated with PnC giant neuron activation. Overall, this work shows that loss of function of the Cntnap2 gene results in increased activity of the PnC and CRNs in rats, contributing to increased acoustic startle response magnitudes.