Serotonin excites fast-spiking interneurons in the striatum

Fast-spiking interneurons (FSIs) control the output of the striatum by mediating feed-forward GABAergic inhibition of projection neurons. Their neuromodulation can therefore critically affect the operation of the basal ganglia. We studied the effects of 5-hydroxytryptamine (5-HT, serotonin), a neurotransmitter released in the striatum by fibres originating in the raphe nuclei, on FSIs recorded with whole-cell techniques in rat brain slices. Bath application of serotonin (30 μm) elicited slow, reversible depolarizations (9 ± 3 mV) in 37/46 FSIs. Similar effects were observed using conventional whole-cell and gramicidin perforated-patch techniques. The serotonin effects persisted in the presence of tetrodotoxin and were mediated by 5-HT2C receptors, as they were reversed by the 5-HT2 receptor antagonist ketanserin and by the selective 5-HT2C receptor antagonist RS 102221. Serotonin-induced depolarizations were not accompanied by a significant change in FSI input resistance. Serotonin caused the appearance of spontaneous firing in a minority (5/35) of responsive FSIs, whereas it strongly increased FSI excitability in each of the remaining responsive FSIs, significantly decreasing the latency of the first spike evoked by a current step and increasing spike frequency. Voltage-clamp experiments revealed that serotonin suppressed a current that reversed around −100 mV and displayed a marked inward rectification, a finding that explains the lack of effects of serotonin on input resistance. Consistently, the effects of serotonin were completely occluded by low concentrations of extracellular barium, which selectively blocks Kir2 channels. We concluded that the excitatory effects of serotonin on FSIs were mediated by 5-HT2C receptors and involved suppression of an inwardly rectifying K+ current

Serotonergic signalling suppresses ataxin 3 aggregation and neurotoxicity in animal models of Machado-Joseph disease

Polyglutamine diseases are a class of dominantly inherited neurodegenerative disorders for which there is no effective treatment. Here we provide evidence that activation of serotonergic signalling is beneficial in animal models of Machado-Joseph disease. We identified citalopram, a selective serotonin reuptake inhibitor, in a small molecule screen of FDA-approved drugs that rescued neuronal dysfunction and reduced aggregation using a Caenorhabditis elegans model of mutant ataxin 3-induced neurotoxicity. MOD-5, the C. elegans orthologue of the serotonin transporter and cellular target of citalopram, and the serotonin receptors SER-1 and SER-4 were strong genetic modifiers of ataxin 3 neurotoxicity and necessary for therapeutic efficacy. Moreover, chronic treatment of CMVMJD135 mice with citalopram significantly reduced ataxin 3 neuronal inclusions and astrogliosis, rescued diminished body weight and strikingly ameliorated motor symptoms. These results suggest that small molecule modulation of serotonergic signalling represents a promising therapeutic target for Machado-Joseph disease.This work was supported by Fundação para a Ciência e Tecnologia (FCT) and COMPETE through the projects ‘[PTDC/SAU-GMG/112617/2009] (to P.M.) and [EXPL/ BIM-MEC/0239/2012] (to A.T.C.)’, by National Ataxia foundation (to P.M.), by Ataxia UK (to P.M.), by National Institutes of Health (NIH) ‘[GM038109, GM081192, AG026647, and NS047331] (to R.I.M.)’, by The Chicago Biomedical Consortium (to R.I.M.) and by the Ellison Medical Foundation (to R.I.M.). A.T.C., A.J., S.E., L.S.S., C.B., S.D.S., A.S.F. and A.N.C. were supported by the FCT individual fellowships SFRH/BPD/79469/2011, SFRH/BD/76613/2011, SFRH/BD/78554/2011, SFRH/BD/ 84650/2012, SFRH/BPD/74452/2010, SFRH/BD/78388/ 2011, SFRH/BPD/91562/2012 and SFRH/BD/51059/2010, respectively. FCT fellowships are co-financed by POPH, QREN, Governo da República Portuguesa and EU/FSE.info:eu-repo/semantics/publishedVersio

In silico Hierarchical Clustering of Neuronal Populations in the Rat Ventral Tegmental Area Based on Extracellular Electrophysiological Properties.

The ventral tegmental area (VTA) is a heterogeneous brain region, containing different neuronal populations. During recordings, electrophysiological characteristics are classically used to distinguish the different populations. However, the VTA is also considered as a region harboring neurons with heterogeneous properties. In the present study, we aimed to classify VTA neurons using approaches, in an attempt to determine if homogeneous populations could be extracted. Thus, we recorded 291 VTA neurons during extracellular recordings in anesthetized rats. Initially, 22 neurons with high firing rates (>10 Hz) and short-lasting action potentials (AP) were considered as a separate subpopulation, in light of previous studies. To segregate the remaining 269 neurons, presumably dopaminergic (DA), we performed analyses, using a combination of different electrophysiological parameters. These parameters included: (1) firing rate; (2) firing rate coefficient of variation (CV); (3) percentage of spikes in a burst; (4) AP duration; (5) Δt duration (i.e., time from initiation of depolarization until end of repolarization); and (6) presence of a notched AP waveform. Unsupervised hierarchical clustering revealed two neuronal populations that differed in their bursting activities. The largest population presented low bursting activities (17.5%). Within non-high-firing neurons, a large heterogeneity was noted concerning AP characteristics. In conclusion, this analysis based on conventional electrophysiological criteria clustered two subpopulations of putative DA VTA neurons that are distinguishable by their firing patterns (firing rates and bursting activities) but not their AP properties

Effects of sustained serotonin reuptake inhibition on the firing of dopamine neurons in the rat ventral tegmental area

Background: Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are efficacious in depression because of their ability to increase 5-HT neurotransmission. However, owing to a purported inhibitory effect of 5- HT on dopamine (DA) neuronal activity in the ventral tegmental area (VTA), this increase in 5- HT transmission might result in a suppression of the firing activity of DA neurons. Since the mesolimbic DA system plays an important role in motivation and reward, a potential decrease in the firing of DA neurons may lead, in some patients, to a lack of adequate response to SSRIs. Methods: We administered the SSRIs citalopram or escitalopram in rats. We determined DA neuronal activity using in-vivo electrophysiology. Results: Sustained administration of escitalopram robustly decreased the firing rate and burst activity of DA neurons. There was no difference in the mean number of spontaneously active DA neurons per tract among the 3 groups (citalopram, escitalopram, control). This inhibition was reversed by the selective 5-HT(20) receptor antagonist SB 242084. Citalopram, however, did not alter the overall firing rate but inhibited the burst activity of DA neurons. Limitations: Our experiments were carried out with the rats under general anesthesia. Therefore, under such conditions the absolute changes produced by SSRIs may heve been different from those occurring in freely moving rats. The exact location of the 5-HT(20) receptors mediating the inhibitory effects of the SSRIs could not be determined in these studies. Conclusion: The difference between escitalopram and citalopram in their effect on DA neuronal activity may be explained by the higher efficacy of escitalopram as a 5- HT reuptake inhibitor. Since the inhibitory effect of escitalopram on DA neuronal activity is mediated via 5-HT(20) receptors, antagonists of these receptors might be effective adjuncts in SSRI-resistant depression