Synaptic architecture of the acoustic startle response pathway

The acoustic startle response (ASR) is mediated by a simple pathway which includes the giant neurons of the caudal pontine reticular nucleus (PnC). Habituation is theorized to occur via hyperpolarizing big potassium (BK) channels localized at glutamatergic terminals of auditory afferents in the PnC. Prepulse inhibition is suggested to be mediated by cholinergic innervation of PnC giant neurons, with possible glutamate and/or GABA co-release. Animals were injected with Fluorogold at C3/C4 to label a subpopulation of PnC giant neurons, and following a startle experiment, brainstems were processed for pCREB expression. Using their respective markers, BK channels, glutamatergic, GABAergic, and cholinergic terminals were also stained. pCREB expression overlapped with retrogradely-labeled PnC giant neurons of startled animals but not controls, supporting their startle-mediating role. Dual-staining shows some BK channel expression on glutamatergic terminals and glutamate/GABA co-expression in a subpopulation of cholinergic terminals which validate their respective implications in habituation or prepulse inhibition of startle

BK Channels Mediate Synaptic Plasticity Underlying Habituation in Rats

Habituation is a basic form of implicit learning and represents a sensory filter that is disrupted in autism, schizophrenia, and several other mental disorders. Despite extensive research in the past decades on habituation of startle and other escape responses, the underlying neural mechanisms are still not fully understood. There is evidence from previous studies indicating that BK channels might play a critical role in habituation. We here used a wide array of approaches to test this hypothesis. We show that BK channel activation and subsequent phosphorylation of these channels are essential for synaptic depression presumably underlying startle habituation in rats, using patch-clamp recordings and voltage-sensitive dye imaging in slices. Furthermore, positive modulation of BK channels in vivo can enhance short-term habituation. Although results using different approaches do not always perfectly align, together they provide convincing evidence for a crucial role of BK channel phosphorylation in synaptic depression underlying short-term habituation of startle. We also show that this mechanism can be targeted to enhance short-term habituation and therefore to potentially ameliorate sensory filtering deficits associated with psychiatric disorders