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Wiring and Volume Transmission: An Overview of the Dual Modality for Serotonin Neurotransmission
Get PDFSerotonin is a neurotransmitter involved in the modulation of a multitude of physiological and behavioral processes. In spite of the relatively reduced number of serotonin-producing neurons present in the mammalian CNS, a complex long-range projection system provides profuse innervation to the whole brain. Heterogeneity of serotonin receptors, grouped in seven families, and their spatiotemporal expression pattern account for its widespread impact. Although neuronal communication occurs primarily at tiny gaps called synapses, wiring transmission, another mechanism based on extrasynaptic diffusion of neuroactive molecules and referred to as volume transmission, has been described. While wiring transmission is a rapid and specific one-to-one modality of communication, volume transmission is a broader and slower mode in which a single element can simultaneously act on several different targets in a one-to-many mode. Some experimental evidence regarding ultrastructural features, extrasynaptic localization of receptors and transporters, and serotonin-glia interactions collected over the past four decades supports the existence of a serotonergic system of a dual modality of neurotransmission, in which wiring and volume transmission coexist. To date, in spite of the radical difference in the two modalities, limited information is available on the way they are coordinated to mediate the specific activities in which serotonin participates. Understanding how wiring and volume transmission modalities contribute to serotonergic neurotransmission is of utmost relevance for the comprehension of serotonin functions in both physiological and pathological conditions
Perché Mario R. Capecchi, Martin J. Evans e Oliver Smithies hanno ricevuto il Premio Nobel 2007 per la fisiologia e la medicina?
No full textHomeobox gene mutations and brain-stem developmental disorders: learning from knockout mice
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A rabies virus based approach to map serotonergic neurons innervating different brain structures
No full textSerotonergic neurons are part of one of the most widely distributed neural systems in the mammalian brain (Lauder and Bloom, 1974). Serotonergic neurons form the raphe nuclei in the brain stem, and are organized in distinct nuclei (B1-9) that project to the whole central nervous system. Consistently with such a broad innervation, serotonin is involved in a wide range of physiological processes including the control of appetite, sleep, memory, mood, stress and sexual behavior (Veenstra-Vanderweele et al, 2000). Several studies using anatomical tracing methods and anterograde viral tracers have led to the hypotheses of a topographic organization of the serotonergic system, with different projections from the caudal, median/central and dorsal raphe neurons to specific target districts in the rostral brain (Muzerelle et al. 2014). Experimental evidence suggests that clusters of serotonergic neurons within the raphe nuclei may have distinct functional properties, but the complex organization of serotonergic neuron projections remains poorly understood. The aim of the present study is to map at a finer scale the organization of serotonin neurons projecting to different target areas, thus contributing to understanding the functional role of specific serotonergic neuronal subpopulations. To this end, we used a Tph2::GFP knock-in mouse model, in which serotonergic neurons are clearly labeled by the expression of GFP (Migliarini et al, 2013), and the retrograde recombinant rabies viral tracer to map the serotonergic neurons innervating different brain structures. Moreover, we developed a conditional GFP expressing mouse model, in which the reporter is maintained under the transcriptional control of the Tph2 gene and activated upon an flp mediated somatic recombination, to map the organization of serotonergic neuron subgroups sharing common targets in the brain
Generation of a Tph2/EGFP knockin mouse line for the study of the role of serotonin during the central nervous system development
No full textWiring transmission in the serotonergic system
No full textSerotonergic neurons are part of one of the most widely distributed systems of the mammalian brain. Indeed, serotonin is involved in a wide range of physiological processes, including the control of appetite, sleep, memory, mood, stress and sexual behavior. The raphe nuclei (B1-9) of the brain stem are the origin of serotonergic projections to the whole central nervous system. In the last years, several studies have unraveled the heterogeneity of serotonergic neurons, in terms of developmental programs, molecular and electrophysiological properties. Recently, a map of the complex topographical organization of the serotonergic fibers has been drawn using intersectional fate mapping strategy, as well as retrograde or anterograde tracing (Bang et al, 2012; Fernandez et al. 2015; Muzerelle et al, 2014). Serotonergic neurons have un-myelinated fiber varicosities, where the transmitter is synthesized, stored and released in a “volume transmission” (VT) mode (Agnati et al, 1995). To a lesser extent, serotonergic fibers also present synapse-like specializations where synaptic contacts are established by 5-HT terminals with specific neuronal targets acting in a conventional “wiring transmission” (WT) mode. However, experimental strategies used to map serotonergic projections so far where not selective for VT versus WT, and the organization of WT is still the object of investigation. Taking advantage of the properties of the rabies virus, whose envelope can drive the infection of neurons exclusively through their presynaptic terminals, we have selectively mapped the serotonergic WT system originating in the raphe nuclei. We injected recombinant G-deleted rabies virus in several brain regions of Tph2::GFP knock-in mice, in which serotonergic neurons were clearly labeled by the expression of GFP (Migliarini et al, 2013). We also used monosynaptic tracing, coupling pseudotyped recombinant rabies virus with a helper adeno-associated virus (Wall et al, 2010). This experimental approach revealed that each brain district hereby investigated receives WT from a relatively small and region-specific number of serotonergic neurons, thus making it possible to establish a correlation map between specific serotonergic neurons in the raphe nuclei and distinct brain areas. Altogether, this study sheds new light on communication properties of serotonergic system, and may help understand the selective role of serotonergic WT in health and disease
Depression-like behavior and response to chronic stress in mice lacking brain serotonin
No full textDuring their lives, virtually all living organisms have to face disturbing forces that upset their homeostasis. These forces, called stressors, trigger a stress response, an innate adaptive response whose task is restoring normal balance of the organism, essential for survival. In vertebrates the brain is central in the adaptation to stress, both in the perception of the stressors and in the organization of the stress response. However, due to a combination of genetic factors and environmental agents, not always a stress response is able to face the stressors, and a maladaptive stress response further destabilizes animal homeostasis, generating stress-related neuropsychiatric disorders such as depression and anxiety. Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that has a central role in normal brain function modulating several physiological processes including mood regulation and emotional behavior, and it has been implicated both in an adaptive and maladaptive stress response. Indeed, several polymorphisms identified in genes involved in serotonin signaling are associated with neuropsychiatric diseases such as depression and anxiety. Moreover, according to the monoamine hypothesis of depression, a reduction of serotonin signaling could be one of the major causes. Current antidepressants act on serotonergic signaling, elevating 5-HT concentration in the synaptic cleft, and showing therapeutic effects 2 to 4 weeks after administration, with a considerable number of patients resistant to the treatment. Therefore, the precise role of serotonin in the modulation of emotional behavior in health and disease needs to be further elucidated. We used a Tph2 knock-out mouse model to evaluate the consequences of brain serotonin depletion on the emotional behavior testing adult animals for behavioral despair. Tph2 mutant mice displayed reduced depression-like behaviors in the forced swim test, in the tail suspension test, as well as in the novelty food suppressed test. We then asked how exposure to Unpredictable Chronic Mild Stress (UCMS), an effective paradigm for inducing depression-like symptoms in rodents, could influence the behavior of animals lacking brain serotonin. Results showed that UCMS induces depressive-like behavior in the forced swim test in both Tph2 -/- and control littermates with a greater increase in immobility between non-stressed and stressed mutant mice than between non-stressed and stressed wt animals. Finally, we are currently treating stressed Tph2 -/- mice with ketamine, a NMDA-R antagonist with rapid and effective antidepressant action, in order to asses if 5-HT is required for its therapeutic effect
Imbalance of serotonin homeostasis during adulthood affects serotonergic neuronal circuitry
No full textSerotonin (5-hydroxytryptamnine, 5-HT) is a monoaminergic neurotransmitter orchestrating a broad array of cognitive and behavioral processes in the adult brain. The early expression of its receptors during development and the requirement of maternal and placental sources of serotonin to the foetus have led to the hypothesis that 5-HT could act as growth regulator in the fine-tuning of specific morphogenetic events during neurodevelopment. Outcomes from genetic mouse models in which brain 5-HT homeostasis has been perturbed by targeting genes necessary for serotonin reuptake, metabolism or synthesis such as SERT, MAO-A and Tph2, respectively, support this hypothesis. However, evidence of a role for 5-HT in adulthood as a growth regulator or its requirement for maintenance of the proper neuronal circuitry, which is known to be susceptible to 5-HT imbalance during early postnatal stages, is still missing. To bridge this gap we used the Tph2 conditional knock-out (cKO) allele that allows an efficient abrogation of 5-HT synthesis in the adult brain, in combination with the Tph2::GFP allele, in which GFP reporter expression highlights 5-HT neuron fibers and somata. Beside previously reported data showing that the lack of brain serotonin in Tph2 knock-out (KO) mice deeply affects serotonergic circuitry development with a brain region-specific effect, the abrogation of 5-HT synthesis during adulthood produces alterations of serotonergic innervation in rostral brain targets matching those observed in mice with a life-long depletion of brain serotonin. Remarkably, we reported that restoring brain 5-HT signaling in both Tph2 KO and cKO mice by chronic administration of the serotonin precursor 5-hydroxytryptophan (5-HTP) results in a significant reduction in the extent of serotonergic fiber innervation defects, thus demonstrating an unexpectedly high degree of plasticity of the adult serotonergic system in response to changes of 5-HT homeostasis. Moreover, 3D computer-based analysis of serotonergic axon terminal morphology showed that imbalances in brain 5-HT content exert their growth regulatory activity on 5-HT axon terminals by promoting sprouting. Altogether these data demonstrate that a correct 5-HT homeostasis is life-long required to maintain the proper serotonergic innervation of specific rostral brain regions
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