Nitric oxide-soluble guanylyl cyclase signaling regulates corticostriatal transmission and short-term synaptic plasticity of striatal projection neurons recorded in vivo.

Striatal medium-sized spiny neurons (MSNs) contain the highest levels of soluble guanylyl cyclase (sGC) in the brain. Striatal sGC signaling is activated by nitric oxide (NO) and other neuromodulators. MSNs also express cGMP-dependent protein kinase and other components of the cGMP signaling system which are critically involved in integrating corticostriatal transmission and regulating synaptic plasticity in striatal networks. However, the influence of tonic and phasic activation of this signaling pathway on striatal MSN activity is poorly understood. The present study examined the impact of systemic administration of the selective sGC inhibitor [1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one] (ODQ) on spike activity evoked using low and high frequency electrical stimulation of the frontal cortex. MSN activity was monitored using single-unit extracellular recordings in urethane-anesthetized rats. ODQ administration significantly decreased spike activity evoked by low frequency cortical stimulation in a stimulus intensity- and time-dependent manner. Additionally, ODQ administered along with the neuronal NO synthase inhibitor 7-nitroindazole (7-NI) potently decreased the incidence of excitatory responses observed during high-frequency train stimulation of the contralateral frontal cortex. The short-term depression of cortically-evoked spike activity induced by train stimulation was enhanced following pretreatment with ODQ in MSNs exhibiting an excitatory response during cortical train stimulation. Unexpectedly, this effect of ODQ was reversed in animals receiving co-administration of ODQ and 7-NI. 7-NI/ODQ co-administration also reversed measures of short-term depression observed in MSNs exhibiting an inhibitory response during cortical train stimulation. These observations extend previous studies showing that tonic and phasic NO-sGC signaling modulates the responsiveness of MSNs to corticostriatal input. Moreover, phasic activation of NO signaling is likely to regulate short-term changes in corticostriatal synaptic plasticity via complex mechanisms involving both sGC-cGMP-dependent and independent pathways. Copyright 2009 Elsevier Ltd. All rights reserved.