A postsynaptic mechanism for dopamine modulation of prepulse inhibition in the goldfish startle circuit.

MEDAN, VIOLETA; PREUSS, THOMAS

Congreso; 40th Annual Meeting of the Society for Neuroscience; 2010

Society for Neuroscience

Prepulse inhibition (PPI) is a sensory gating phenomenon characterized by adecrease in magnitude of a startle reflex if a weak stimulus is presented20-500 ms before the startling stimulus. PPI is used as a research anddiagnostic tool for several neurological disorders and neuropharmacologyexperiments have identified several neurotransmitters that modulate PPI. Forexample, dopaminergic agonists such as apomorphine disrupt behavioralPPI, which provides an important neurobiological link to comparable PPIdeficits in schizophrenic patients. However the neural substrates and thecellular mechanisms that mediate this modulation have not yet beenidentified. In vertebrates, PPI is produced within homolog reticulospinalstartle circuits allowing a comparative approach to study this phenomenon.Indeed, teleost fish display PPI-type attenuation and a correspondingattenuation of the synaptic response in an identifiable reticulospinal neuron,the Mauthner-cell (M-cell), which integrates sensory information andtriggers the startle escape behavior. This neuron is accessible for in vivoelectrophysiology, which allowed to test the hypothesis that apomorphineeffects PPI at the level of the elementary startle circuit.We recorded M-cell PSPs to pairs of sound pulses with inter-stimulusintervals (ISIs) of 20, 50, 150 or 500 ms before and after systemic injectionsof dopaminergic agents. Apomorphine (2mg/kg bw) reduced PPI for 50ISI a25% (p=0.01, N=13) while other ISIs show slight or no reduction. Dynamiccurrent injections while recoding M-cell membrane potential revealed thatthe dopamine affects a M-cell membrane non-linearity indicated by anincrease in input resistance for membrane depolarization above 6mV. Thisincrease is most pronounced for 50ISI (30.3%, N=4, p<0.01) but remainselevated for at least 500ISI (27.7%, N=4, p=0.04). Consistently, applicationof the dopamine antagonist haloperidol (0.4mg/kg bw) restores PPI tocontrol level. In addition, apomorphine produces a shift in input resistancefrom 113±19 to 136±26 KΩ (mean 20.04%, N=4) not related to PPI.Taken together these results demonstrate for the first time, a postsynapticmechanism that mediates dopaminergic modulation of PPI in the elementarystartle circuit of vertebrates. Better understanding of mechanisms of PPI andits neuromodulation might help to develop a more targeted pharmacologicaltreatment of sensory-gating disorders.