Dopaminergic-induced changes in Mauthner cell excitability disrupt prepulse inhibition in the startle circuit of goldfish

Abstract

Medan V, Preuss T. Dopaminergic-induced changes in Mauthner cell excitability disrupt prepulse inhibition in the startle circuit of goldfish. J Neurophysiol 106: 3195-3204, 2011. First published September 28, 2011 doi:10.1152/jn.00644.2011.-Prepulse inhibition (PPI) is a widespread sensorimotor gating phenomenon characterized by a decrease in startle magnitude if a nonstartling stimulus is presented 20 -1,000 ms before a startling stimulus. Dopaminergic agonists disrupt behavioral PPI in various animal models. This provides an important neuropharmacological link to schizophrenia patients that typically show PPI deficits at distinct (60 ms) prepulsepulse intervals. Here, we study time-dependent effects of dopaminergic modulation in the goldfish Mauthner cell (M-cell) startle network, which shows PPI-like behavioral and physiological startle attenuations. The unique experimental accessibility of the M-cell system allows investigating the underlying cellular mechanism with physiological stimuli in vivo. Our results show that the dopaminergic agonist apomorphine (2 mg/kg body wt) reduced synaptic M-cell PPI by 23.6% (n ϭ 18; P ϭ 0.009) for prepulse-pulse intervals of 50 ms, whereas other intervals showed no reduction. Consistently, application of the dopamine antagonist haloperidol (0.4 mg/kg body wt) restored PPI to control level. Current ramp injections while recording M-cell membrane potential revealed that apomorphine acts through a postsynaptic, time-dependent mechanism by deinactivating a M-cell membrane nonlinearity, effectively increasing input resistance close to threshold. This increase is most pronounced for prepulse-pulse intervals of 50 ms (47.9%, n ϭ 8; P Ͻ 0.05) providing a timedependent, cellular mechanism for dopaminergic disruption of PPI. These results provide, for the first time, direct evidence of dopaminergic modulation of PPI in the elementary startle circuit of vertebrates and reemphasize the potential of characterizing temporal aspects of PPI at the physiological level to understand its underlying mechanisms.sensorimotor-gating; dopamine; cellular mechanisms; input resistance; time-specific neuromodulation THE CENTRAL NERVOUS SYSTEM has to filter the overwhelming stream of information provided by the various sense organs while optimizing detection of behaviorally relevant information. One prominent filtering phenomenon is prepulse inhibition (PPI), which is thought of as an early sensory gate that reduces the sensory information of a secondary event (pulse) while a preceding event (prepulse) is being processed (Graham 1975;Hoffman and Ison 1980;Koch 1999). Experimentally, PPI is produced when a startling stimulus (pulse) is preceded within 20 -1,000 ms by a subthreshold stimulus (prepulse) of the same or another modality (Graham 1975;Hoffman and Ison 1980;Koch 1999). The multimodal nature of PPI distinguishes it from unimodal synaptic modulations such as pairedpulse depression and short-term habituation (Aubert et al. 2006;Campeau and Davis 1995;Simons-Weidenmaier et al. 2006). The majority ...

Functional Effects of Schizophrenia-Linked Genetic Variants on Intrinsic Single-Neuron Excitability: A Modeling Study

“…Although the shown effect was partly attributed to the differences in the spiking thresholds between the variants, differences between the variants could still be observed when absolute spiking threshold values for inducing a second spike were considered (data not shown). These findings raise the possibility that the disturbed prepulse inhibition observed in many SCZ patients might be an effect of altered ionic channel properties at the single-neuron level and not only of the modified elements in synaptic circuitry as previously thought (21,22) [cf. (23)].…”

Differential processing in modality‐specific Mauthner cell dendrites

“…Inactivation of this conductance progressively increases M‐cell input resistance as its membrane potential approaches firing threshold (Faber & Korn, ; Neumeister et al . ; Medan & Preuss, ). However, it is not known whether the membrane of the VD contains similar conductance(s).…”

“…Intracellular responses of the M‐cell to visual and acoustic stimuli were studied in vivo using standard surgical and electrophysiological recording techniques (Preuss & Faber, ; Preuss et al . ; Medan & Preuss, ). To initiate anaesthesia, fish were immersed in ice water (1 litre) with 40 mg l −1 of the general anaesthetic tricaine methanesulfonate (MS‐222), until fish ceased to swim, lost equilibrium and were unresponsive to a pinch on the tail (typically 10–15 min).…”

“…This membrane nonlinearity can be characterized in a standardized way by injecting a positive current ramp (0–150 nA/20 ms; Wavetek Model 39) into the cell while recording membrane voltage with a second electrode (Neumeister et al . ; Medan & Preuss ). The resulting I – V plots reveal activation and inactivation of voltage‐dependent conductances over the entire range of membrane depolarization as a corresponding decrease and increase in membrane resistance, respectively.…”

Progressively Increased M50 Responses to Repeated Sounds in Autism Spectrum Disorder with Auditory Hypersensitivity: A Magnetoencephalographic Study

“…Serotonin 5-HT5A contributes to sensorimotor integration and decision-making by directly regulating excitability. Moreover, Medan and Preuss [24] found that dopaminergic modulation regulates the time course and magnitude of PPI, whereas 5-HT regulates tonic excitability. Many studies have found abnormalities in the serotonin/dopamine system in autism patients [25], [26].…”