Plasticity of Fetal and Adult CNS Serotonergic Neurons: Role of Growth‐Regulatory Factors<sup>a</sup>

Azmitia, Efrain C.; Frankfurt, Maya; Dávila, Martha; Whitaker‐Azmitia, Patricia M.; Zhou, Feng

doi:10.1111/j.1749-6632.1990.tb16894.x

Cited by 28 publications

(13 citation statements)

References 69 publications

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“…Studies of IGC fractions obtained from early rat brain suggest that growth cones are unable to secrete 5-HT before they acquire vesicles of the synaptic type (Lockerbie et al,199 1). The present observation, however, that synaptic vesicles appear in serotonergic neurons before synaptogenesis, and evidence that 5-HT can be secreted by growing axons (Reisert et al, 1989;Ugrumov et al, 1989;Azmitia et al, 1990) are consistent with the idea that 5-HT plays a role in development (Lauder and Krebs, 1978;Lauder et al, 1988;Hamon et al, 1989;Lauder 1991). 5-HT, for example, has been shown to be a stop signal for growth cones in developing snail ganglia, halting neurite elongation and synapse formation (Haydon et al, 1987;McCobb et al, 1988).…”

Section: Discussionsupporting

confidence: 89%

Synaptic properties of serotonergic growth cones in developing rat brain

1994

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In order to gain insight into the events that take place when serotonergic growth cones are remodeled into synapses, we tested the hypothesis that neurotransmitter-related properties of presynaptic terminals are already present in these growth cones before synaptogenesis begins. The ontogeny of markers for the specific reuptake of 5-HT and for 5-HT-storing synaptic vesicles was studied in isolated growth cone (IGC) fractions from developing rat brain. High- affinity 3H-imipramine binding (a marker for the plasma membrane 5-HT transporter) was significantly enriched in IGC fractions prepared before the beginning of cortical synaptogenesis [embryonic day 15 (E15) and E20]. Radioautography with 3H-imipramine or 3H-paroxetine (another marker for the transporter) confirmed that the 5-HT transporter is present in the cerebral cortex when it contains serotonergic growth cones, but not serotonergic synapses. Specific uptake of 3H-5-HT was found in IGC fractions as early as E15; this uptake was inhibited by fluoxetine. Electron microscopic radioautography demonstrated directly that growth cones were the structures in IGC fractions that took up 3H- 5-HT. The synaptic vesicle protein synaptophysin and a 45 kDa protein found specifically in serotonergic synaptic vesicles, serotonin-binding protein (SBP), were each enriched in IGC fractions from E15 to postnatal day 5; SBP immunoreactivity increased approximately 10-fold between E15 and E20. Endogenous 5-HT was detected in IGC fractions at E15 and increased in amount as development proceeded. The ratio of 5-HT to 5-hydroxyindole acetic acid suggested that 5-HT within growth cones is protected from catabolism by monoamine oxidase. Reserpine-induced depletion of 5-HT, a marker for the vesicular carrier of 5-HT, was apparent in IGC fractions at E20, but not at E15. These data suggest that properties that characterize the presynaptic components of mature serotonergic synapses develop in growth cones before synapses are formed. The early development of these properties may permit neurotransmission to be established rapidly during synaptogenesis or, alternatively, enable 5-HT to play a role in ontogeny.

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Section: Discussionsupporting

confidence: 89%

Synaptic properties of serotonergic growth cones in developing rat brain

1994

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“…4). This regrowth-promoting effect is probably due to a 5-HT-mediated increase in the production and release of astrocytic growth factors which are known to stimulate the outgrowth of 5-HT nerve endings even in the adult brain (Azmitia et al, 1990a;Whittaker-Azmitia et al, 1990). One important argument underlines the need for early and effective treatments which support the regeneration of 5-HT nerve terminals: The loss of serotonergic nerve endings represents only the first step in a sequence of events, which will inevitably lead to the destabilization of these neuronal circuits and synaptic connections in local neuronal networks which are normally stabilized by serotonergic inputs.…”

Section: Consequences Of the Loss Of 5-ht-afferencesmentioning

confidence: 96%

Causes and consequences of the loss of serotonergic presynapses elicited by the consumption of 3,4-methylenedioxymethamphetamine (MDMA, ?ecstasy?) and its congeners

Huether

Zhou

Rüther

1997

J. Neural Transmission

125

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The massive and prolonged stimulation of serotonin (5-HT)-release and the increased dopaminergic activity are responsible for the acute psychomimetic and psychostimulatory effects of 3,4-methylenedioxy-methamphetamine (MDMA, "ecstasy") and its congeners. In vulnerable subjects, at high doses or repeated use, and under certain unfavorable conditions (crowding, high ambient temperature), severe, in some cases fatal, averse systemic reactions (hyperthermia, serotonin-syndrome) may occur during the first few hours. Animal experiments revealed the existence of similar differences in vulnerability and similar dose- and context-related influences on a similar sequence of acute responses. The severity of these acute systemic responses is closely related to the severity of the long-term damage to 5-HT axon terminals caused by the administration of substituted amphetamines. Attempts to identify the mechanisms involved in this selective degeneration of 5-HT presynapses brought to light a multitude of different factors and conditions which either attenuate or potentiate the loss of 5-HT terminals caused by MDMA and related amphetamine derivatives. These puzzling observations suggest that the degeneration of 5-HT presynapses represents only the final step in a sequence of events which compromise the ability of 5-HT terminals to maintain their functional and structural integrity. Substituted amphetamines selectively tax energy metabolism in 5-HT presynapses through their ability to exchange with 5-HT and to dissipate transmembrane ion gradients. The active carrier systems in the vesicular and presynaptic membrane operate at a permanently activated state. The resulting energy deficit can no longer adequately restored by the 5-HT presynapses when their availability of substrates for ATP production is additionally reduced by the hyperthermic and other energy consuming reactions which are elicited by the systemic administration of substituted amphetamines. The exhaustion of energy in 5-HT nerve terminals compromised all energy-requiring endogenous mechanisms involved in the regulation of transmembrane-ion exchange, internal Ca(++)-homeostasis, prevention of oxidative stress, detoxification, and repair. Above a critical threshold the failure of these self-protective mechanisms will lead to the degeneration of the 5-HT axon terminals. Based on the role of 5-HT as a global modulatory transmitter-system involved in the stabilization and integration of impulse flow between distributed multifocal neuronal networks, the partial loss of 5-HT presynapses must be expected to impair the ability of these networks to maintain the integrity of signal flow pattern, and increase the likelihood of switching to unstable information processing. Behavioral responding may therefore become more dominated by activities generated in individual networks, and hitherto "buffered" personality traits and predisposition may become manifested as defined psychiatric syndromes in certain predisposed subjects.

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“…Moreover, both ACTH, acting through adenyl cyclase, and BDNF interact with depolarization to increase expression of the serotonergic properties of RN46A cells. These effects are also seen in primary cultures of raphe neurons (Azmitia et al, 1990;Suiciak et al, 1994Suiciak et al, , 1998. Here we show that activation of adenyl cyclase also causes down-regulation of GAP-43, opposite to its effect on expression of neurofilament proteins and serotonergic markers, and consistent with the concept of a global switch to a more mature phenotype.…”

Section: Camp Regulates Gap-43 and Neurite Growthmentioning

confidence: 79%

Divergent regulation of GAP-43 expression and CNS neurite outgrowth by cyclic AMP

Andersen¹,

Webber²,

Whittemore³

et al. 2000

J. Neurosci. Res.

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Plasticity of Fetal and Adult CNS Serotonergic Neurons: Role of Growth‐Regulatory Factors^a

Cited by 28 publications

References 69 publications

Synaptic properties of serotonergic growth cones in developing rat brain

Synaptic properties of serotonergic growth cones in developing rat brain

Causes and consequences of the loss of serotonergic presynapses elicited by the consumption of 3,4-methylenedioxymethamphetamine (MDMA, ?ecstasy?) and its congeners

Divergent regulation of GAP-43 expression and CNS neurite outgrowth by cyclic AMP

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Plasticity of Fetal and Adult CNS Serotonergic Neurons: Role of Growth‐Regulatory Factorsa

Cited by 28 publications

References 69 publications

Synaptic properties of serotonergic growth cones in developing rat brain

Synaptic properties of serotonergic growth cones in developing rat brain

Causes and consequences of the loss of serotonergic presynapses elicited by the consumption of 3,4-methylenedioxymethamphetamine (MDMA, ?ecstasy?) and its congeners

Divergent regulation of GAP-43 expression and CNS neurite outgrowth by cyclic AMP

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Plasticity of Fetal and Adult CNS Serotonergic Neurons: Role of Growth‐Regulatory Factors^a