Altered synaptic depression of auditory input to startle-mediating PnC giant neurons in Cntnap2 KO rats

Cntnap2 knockout (KO) rats show alterations in sensory processing, including greatly enhanced startle reactivity and impaired short-term habituation, reminiscent of autistic individuals. Startle responses and short-term habituation of startle are mediated by short brainstem pathways that include afferent fibers from cochlear (auditory) and trigeminal (tactile) nuclei innervating giant neurons in the caudal pontine reticular nucleus (PnC), which directly innervate spinal motor neurons to elicit startle. In order to better understand the mechanisms underlying changes in startle reactivity in Cntnap2 KO rats, we examined the intrinsic properties and excitability of the PnC neurons, as well as depression in sensorimotor synapses in the PnC, previously shown to underlie habituation. We expected to find higher excitability in Cntnap2 KO rats and/or disruptions in synaptic depression. Furthermore, as the GABA_B receptor agonist R-baclofen has been shown to restore startle habituation in Cntnap2 KO rats, we predicted that it would facilitate synaptic depression. Whole-cell patch-clamp recordings were conducted in PnC giant neurons from WT and Cntnap2 KO rats of both sexes. Synaptic depression was impaired in Cntnap2 KO rats at the auditory but not trigeminal synapses. Notably, R-baclofen impeded synaptic depression but also greatly reduced the amplitudes of evoked EPSCs in both WT and Cntnap2 KOs. These are novel results that provide a potential mechanism for reduced habituation of startle in Cntnap2 KO rats, as well as insights about how R-baclofen impacts the startle pathway. Overall, this study indicates that sensorimotor deficits in ASD may stem from specific synaptic changes in brainstem structures.