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Zhou, F.-M.

Publications and source records attributed to Zhou, F.-M..

2 recordsLinked to original sources
bioRxiv2024

Chronic fluoxetine treatment desensitizes serotoninergic inhibition of GABA inputs and the intrinsic excitability of dorsal raphe serotonin neurons

Dorsal raphe serotonin (5-hydroxytryptamine, 5-HT) neurons are spontaneously active and release 5-HT that is critical to normal brain function such mood and emotion. Serotonin reuptake inhibitors (SSRIs) increase the synaptic and extracellular 5-HT level and are effective in treating depression. Treatment of two weeks or longer is often required for SSRIs to exert clinical benefits. The cellular mechanism underlying this delay was not fully understood. Here we show that the GABAergic inputs inhibit the spike firing of raphe 5-HT neurons; this GABAergic regulation was reduced by 5-HT, which was prevented by G-protein-activated inwardly rectifying potassium (Girk) channel inhibitor tertiapin-Q, indicating a contribution of 5-HT activation of Girk channels in GABAergic presynaptic axon terminals. Equally important, after 14 days of treatment of fluoxetine, a widely used SSRI type antidepressant, this 5-HT inhibition of GABAergic inputs was substantially downregulated. Furthermore, the chronic fluoxetine treatment substantially downregulated the 5-HT activation of the inhibitory Girk current in 5-HT neurons. Taken together, our results suggest that chronic fluoxetine administration, by blocking 5-HT reuptake and hence increasing the extracellular 5-HT level, can downregulate the function of 5-HT1B receptors on the GABAergic afferent axon terminals synapsing onto 5-HT neurons, allowing extrinsic, behaviorally important GABA neurons to more effectively influence 5-HT neurons; simultaneously, chronic fluoxetine treatment also downregulate somatic 5-HT autoreceptor-activated Girk channel-mediated hyperpolarization and decrease in input resistance and intrinsic excitability, rendering 5-HT neurons resistant to autoinhibition and leading to increased 5-HT neuron activity, potentially contributing to the antidepressant effect of SSRIs.

neuroscience↗
bioRxiv2024

Dopaminergic inhibition of the inwardly rectifying potassium current in direct pathway medium spiny neurons in normal and parkinsonian striatum

Despite the profound behavioral effects of the striatal dopamine (DA) activity and the inwardly rectifying potassium channel (Kir) being a key determinant of striatal medium spiny neuron (MSN) activity that also profoundly affects behavior, previously reported DA regulations of Kir are conflicting and incompatible with MSN function in behavior. Here we show that in normal mice with an intact striatal DA system, the predominant effect of DA activation of D1Rs in D1-MSNs is to cause a modest depolarization and increase in input resistance by inhibiting Kir, thus moderately increasing the spike outputs from behavior-promoting D1-MSNs. In parkinsonian (DA-depleted) striatum, DA increases D1-MSN intrinsic excitability more strongly than in normal striatum, consequently strongly increasing D1-MSN spike firing that is behavior-promoting; this DA excitation of D1-MSNs is stronger when the DA depletion is more severe. The DA inhibition of Kir is occluded by the Kir blocker barium chloride (BaCl2). In behaving parkinsonian mice, BaCl2 microinjection into the dorsal striatum stimulates movement but occludes the motor stimulation of D1R agonism. Taken together, our results resolve the long-standing question about what D1R agonism does to D1-MSN excitability in normal and parkinsonian striatum and strongly indicate that D1R inhibition of Kir is a key ion channel mechanism that mediates D1R agonistic behavioral stimulation in normal and parkinsonian animals.

neuroscience↗