Serotonin regulates synaptic connections in the dentate molecular layer of adult rats via 5-HT1a receptors: evidence for a glial mechanism

The present study sought to verify effects of 5-HT on synaptic density at the ultrastructural level, to determine whether the 5-HT1a receptor is important for the maintenance of synaptic connections and to obtain evidence implicating S100 beta in the apparent neurotrophic actions of 5-HT. Reduction of hippocampal 5-HT with para-chloroamphetamine (PCA) resulted in a significant decline in the synaptic density of the dentate molecular layer. Reduction of norepinephrine with DSP-4 produced a slight decrease in the number of molecular layer synapses, but this difference was not statistically different from control values. 5-HT1a antagonist treatment resulted in a decline in synaptic density comparable to that observed following PCA treatment. These observations suggest that 5-HT functions to maintain synaptic connections in the dentate molecular layer via a 5-HT1a mechanism. To determine whether the change in synaptic density was due to the action of 5-HT on neuronal receptors or astrocytic receptors, a monoclonal antibody against S100 beta was infused into the lateral ventricle for seven days. Controls received infusions of normal goat serum. Half of the rats from the anti-S100 beta and control groups also received daily injections of NAN-190. Anti-S100 beta infusion resulted in a significant (p < 0.01) decrease in synapses compared to serum controls. Concomitant NAN-190 administration did not enhance synapse loss in the anti-S100 beta group. The results of this study suggest that the maintenance of synaptic connections in the dentate molecular layer is influenced by S100 beta levels that are controlled by 5-HT stimulation of astrocytic 5-HT1a receptors.

[1]  J. Haring,et al.  Effects of neonatal serotonin depletion on the development of rat dentate granule cells. , 1997, Brain research. Developmental brain research.

[2]  N. Gay,et al.  Inhibition of methionine incorporation into brain proteins after the systemic administration of p-chlorophenylalanine and L-5-hydroxytryptophan. , 1991, European journal of pharmacology.

[3]  E. Azmitia,et al.  5-HT1A agonist and dexamethasone reversal of para-chloroamphetamine induced loss of MAP-2 and synaptophysin immunoreactivity in adult rat brain , 1995, Brain Research.

[4]  E. Azmitia,et al.  Localization of 5‐HT1A receptors to astroglial cells in adult rats: Implications for neuronal‐glial interactions and psychoactive drug mechanism of action , 1993, Synapse.

[5]  W. Greenough,et al.  Astrocytic and synaptic response to kindling in hippocampal subfield CA1. I. Synaptogenesis in response to kindling in vitro , 1993, Brain Research.

[6]  J. Kleim,et al.  Synaptogenesis and FOS Expression in the Motor Cortex of the Adult Rat after Motor Skill Learning , 1996, The Journal of Neuroscience.

[7]  C. Cotman,et al.  Synapse replacement in the nervous system of adult vertebrates. , 1981, Physiological reviews.

[8]  G. Raisman,et al.  Endogenous synaptogenesis in the deafferented dentate gyrus does not exclude synapse formation by embryonic entorhinal transplants , 1997, Brain Research.

[9]  E. Azmitia,et al.  Stimulation of astroglial 5-HT1A receptors releases the serotonergic growth factor, protein S-100, and alters astroglial morphology , 1990, Brain Research.

[10]  P M Field,et al.  A quantitative investigation of the development of collateral reinnervation after partial deafferentation of the septal nuclei. , 1973, Brain research.

[11]  O. Steward,et al.  The process of reinnervation in the dentate gyrus of the adult rat: A quantitative electron microscopic analysis of terminal proliferation and reactive synaptogenesis , 1983 .

[12]  J. Haring,et al.  5-HT1a receptors mediate the neurotrophic effect of serotonin on developing dentate granule cells. , 1997, Brain research. Developmental brain research.

[13]  W. Levy,et al.  Synaptic correlates of associative potentiation/depression: an ultrastructural study in the hippocampus , 1983, Brain Research.

[14]  W. Levy,et al.  Changes in the numerical density of synaptic contacts with long‐term potentiation in the hippocampal dentate gyrus , 1986, The Journal of comparative neurology.

[15]  J. Haring,et al.  Hippocampal serotonin levels influence the expression of S100β detected by immunocytochemistry , 1993, Brain Research.

[16]  R. S. Sloviter.  Possible functional consequences of synaptic reorganization in the dentate gyrus of kainate-treated rats , 1992, Neuroscience Letters.

[17]  S. Hamada,et al.  PCPA reduces both monoaminergic afferents and nonmonoaminergic synapses in the cerebral cortex , 1994, Neuroscience Research.

[18]  W. Levy,et al.  Ovarian steroidal control of connectivity in the female hippocampus: An overview of recent experimental findings and speculations on its functional consequences , 1997, Hippocampus.

[19]  C. de Montigny,et al.  Electrophysiological Investigation of the Adaptive Response of the 5‐HT System to the Administration of 5‐HT1A Receptor Agonists , 1990, Journal of cardiovascular pharmacology.

[20]  E. Azmitia,et al.  Astroglial 5-HT1a receptors and S-100 beta in development and plasticity. , 1994, Perspectives on developmental neurobiology.

[21]  D. Marshak.  S100 beta as a neurotrophic factor. , 1990, Progress in brain research.

[22]  Bruce S. McEwen,et al.  Estradiol and progesterone regulate neuronal structure and synaptic connectivity in adult as well as developing brain , 1994, Experimental Gerontology.