5-HT1a receptors mediate the neurotrophic effect of serotonin on developing dentate granule cells.

We have previously reported that neonatal (P3) serotonin (5-HT) depletion results in a significant decrease in the number of dendritic spines per 50 microns of dendritic length on dentate granule cells. This effect is specific and permanent. Neither total dendritic length nor the number of dendritic segments is affected by 5-HT depletion. The area dentata contains a dense 5-HT1a receptor population that is present in the at birth. Therefore, 5-HT1a receptors represented a likely candidate for the mediation of the effects of 5-HT on developing granule cells. The present study used the drugs buspirone and NAN-190, which have been shown to be an agonist and antagonist respectively at postsynaptic 5-HT1a receptors in vivo, to test the idea that neurotrophic actions of 5-HT result from 5-HT1a receptor stimulation. Following 5-HT depletion with PCA, pups received daily injections of buspirone (1.0 mg/kg) from P5 to P14. Granule cell morphology was then studied using intracellular filling with Neurobiotin on P14, P21 and P60. Buspirone treatment prevented the loss of dendritic spines previously shown to follow 5-HT depletion with PCA. No other morphological parameters were significantly changed by buspirone treatment. Naive pups received daily injections of NAN-190 from P3 to P14. One group received 1.0 mg/kg while a second group received 3.5 mg/kg. Both doses of NAN-190 resulted in dendritic spine loss comparable to that obtained with neonatal PCA treatment. This loss was permanent suggesting that the first two postnatal weeks may represent a critical period for the action of 5-HT on developing granule cells. Significant, dose-dependent changes in total dendritic length and number of dendritic segments reminiscent of the effects of norepinephrine depletion were also observed in NAN-190-treated rats. We suspect that this change is the result of the action NAN-190 at alpha receptors and is therefore distinct from the specific effect of 5-HT on the number of dendritic spines. The NAN-190 experiment also shows that the loss of dendritic spines is a function of decreased stimulation of 5-HT1a receptors and not the loss of 5-HT terminal membrane.

[1]  G. Tunnicliff,et al.  Effects of repeated doses of azapirones on rat brain 5-HT1A receptors and plasma corticosterone levels. , 1996, General pharmacology.

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

[3]  S. Hjorth,et al.  Mixed agonist/antagonist properties of NAN-190 at 5-HT1A receptors: behavioural and in vivo brain microdialysis studies. , 1990, Life sciences.

[4]  E. Azmitia,et al.  [3H]5‐Hydroxytryptamine Binding to Brain Astroglial Cells: Differences Between Intact and Homogenized Preparations and Mature and Immature Cultures , 1986, Journal of neurochemistry.

[5]  R. Glennon,et al.  NAN-190: an arylpiperazine analog that antagonizes the stimulus effects of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). , 1988, European journal of pharmacology.

[6]  J. Haring,et al.  Transient reduction in hippocampal serotonergic innervation after neonatal parachloroamphetamine treatment. , 1994, Brain research. Developmental brain research.

[7]  J. Lauder,et al.  Serotonin as a differentiation signal in early neurogenesis. , 1978, Developmental neuroscience.

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

[9]  M. Millan,et al.  Modulation of the activity of central serotoninergic neurons by novel serotonin1A receptor agonists and antagonists: a comparison to adrenergic and dopaminergic neurons in rats. , 1995, The Journal of pharmacology and experimental therapeutics.

[10]  Patricia Gaspar,et al.  Lack of Barrels in the Somatosensory Cortex of Monoamine Oxidase A–Deficient Mice: Role of a Serotonin Excess during the Critical Period , 1996, Neuron.

[11]  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.

[12]  K. McCarthy,et al.  In vivo and in vitro development of serotonergic neurons , 1982, Brain Research Bulletin.

[13]  Bruce S. McEwen,et al.  Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons , 1990, Brain Research.

[14]  Alan Peters,et al.  A technique for estimating total spine numbers on golgi‐impregnated dendrites , 1979, The Journal of comparative neurology.

[15]  E. Azmitia,et al.  Cellular Localization of the 5-HT1A Receptor in Primate Brain Neurons and Glial Cells , 1996, Neuropsychopharmacology.

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

[17]  R. Glennon,et al.  NAN-190: agonist and antagonist interactions with brain 5-HT1A receptors , 1990, Brain Research.

[18]  Lack of evidence for serotonergic effect on the cellular development of the olfactory bulb in the postnatal rat , 1994, Brain Research Bulletin.

[19]  S. Hjorth,et al.  Sustained 5-hydroxytryptamine release-inhibitory and anxiolytic-like action of the partial 5-HT1A receptor agonist, buspirone, after prolonged chronic administration. , 1993, European journal of pharmacology.

[20]  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.

[21]  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.

[22]  J. Vellis,et al.  Glial-released proteins: III. Influence on neuronal morphological differentiation , 1981, Brain Research.

[23]  G. Buznikov.  The action of neurotransmitters and related substances on early embryogenesis. , 1984, Pharmacology & therapeutics.

[24]  B. Claiborne,et al.  Dendritic growth and regression in rat dentate granule cells during late postnatal development. , 1990, Brain research. Developmental brain research.

[25]  D. Wright,et al.  Comparative localization of serotonin1A, 1C, and 2 receptor subtype mRNAs in rat brain , 1995, The Journal of comparative neurology.

[26]  J. Palacios,et al.  Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors , 1985, Brain Research.

[27]  J. Lauder,et al.  Roles for serotonin in neuroembryogenesis. , 1981, Advances in experimental medicine and biology.

[28]  M. Hamon,et al.  Postnatal development and localization of 5-HT1A receptor mRNA in rat forebrain and cerebellum. , 1994, Brain research. Developmental brain research.

[29]  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.

[30]  D. Jackson,et al.  Development of tolerance to 8-OH-DPAT induced blockade of acquisition of a passive avoidance response , 1994, Neuropharmacology.

[31]  G. V. Konovalov,et al.  The effects of serotonin on the morpho-functional development of rat cerebral neocortex in tissue culture , 1986, Brain Research.

[32]  S. Ross,et al.  Counteraction of the rapid tolerance to 8‐OH‐DPAT‐induced corticosterone secretion in rats by activation of the GABAA receptor‐chloride channel complex , 1993, British journal of pharmacology.

[33]  C. Woolley,et al.  Short-term glucocorticoid manipulations affect neuronal morphology and survival in the adult dentate gyrus , 1990, Neuroscience.

[34]  L. Spear,et al.  5-HT1A, 5-HT1B and 5-HT2 receptor agonists induce differential behavioral responses in neonatal rat pups. , 1988, European journal of pharmacology.

[35]  G. Lynch,et al.  A quantitative electron microscopic study of synaptogenesis in the dentate gyrus of the rat. , 1973, Brain research.

[36]  S. Peroutka,et al.  The Neuropharmacology of Serotonin , 1990 .

[37]  C. Woolley,et al.  Adrenal steroids regulate postnatal development of the rat dentate gyrus: I. Effects of glucocorticoids on cell death , 1991, The Journal of comparative neurology.