Serotonin (5-HT) is an important neurotransmitter expressed in different brain areas. 5-HT is involved in remodeling brain structures and circuits during development, through the modulation of several processes including neural cell proliferation, migration and differentiation, neurite outgrowth, axon guidance and synaptogenesis, control of dendritic spine shape and density. Recently, we have shown that activation of 5-HT7 receptors reverses metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD) in wild-type (WT) and Fmr1 knockout (KO) mice (Costa et al., Biol Psychiatry. 2012, 72(11):924-33), a mouse model of Fragile X syndrome (FXS), which is characterized by an abnormally enhanced mGluR-LTD. Here, we extended our study to the examination of dendritic spine morphology and density, which are abnomal in FXS. We studied the expression of 5-HT7 receptors in synaptic plasma membranes (SPMs) prepared from cortices and hippocampi of WT and Fmr1 KO mice, and found that in SPMs of both regions 5-HT7 receptors are present in the post-synaptic fraction in both genotypes. We tested the effects of an acute systemic administration of the compound LP-211 (3 mg/Kg), a potent, selective and brain-permeant 5-HT7 receptor agonist in WT and Fmr1 KO mice. We evaluated dendritic spine density and morphology in the cortex and the CA1-CA3 areas of hippocampus by analyzing confocal microscopy images from slices labeled with the lypophilic tracer DiI. Our results indicate an increased spine density in both cortex and hippocampus in Fmr1 KO mice, which was not detected after LP-211 administration in both brain regions. Interestingly, the reduction of spine density in LP-211-treated Fmr1 KO mice affected thin spines. Our data suggest that in vivo administration of a selective agonist of 5-HT7 receptors results in the correction of increased spine density, a hallmark feature of FXS, suggesting that targeting of 5-HT7 receptors might be considered as a new therapeutic strategy for FXS.
Effect of 5-HT7 receptor activation on dendritic spines in wild-type and Fmr1 knockout mice
2015
Abstract
Serotonin (5-HT) is an important neurotransmitter expressed in different brain areas. 5-HT is involved in remodeling brain structures and circuits during development, through the modulation of several processes including neural cell proliferation, migration and differentiation, neurite outgrowth, axon guidance and synaptogenesis, control of dendritic spine shape and density. Recently, we have shown that activation of 5-HT7 receptors reverses metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD) in wild-type (WT) and Fmr1 knockout (KO) mice (Costa et al., Biol Psychiatry. 2012, 72(11):924-33), a mouse model of Fragile X syndrome (FXS), which is characterized by an abnormally enhanced mGluR-LTD. Here, we extended our study to the examination of dendritic spine morphology and density, which are abnomal in FXS. We studied the expression of 5-HT7 receptors in synaptic plasma membranes (SPMs) prepared from cortices and hippocampi of WT and Fmr1 KO mice, and found that in SPMs of both regions 5-HT7 receptors are present in the post-synaptic fraction in both genotypes. We tested the effects of an acute systemic administration of the compound LP-211 (3 mg/Kg), a potent, selective and brain-permeant 5-HT7 receptor agonist in WT and Fmr1 KO mice. We evaluated dendritic spine density and morphology in the cortex and the CA1-CA3 areas of hippocampus by analyzing confocal microscopy images from slices labeled with the lypophilic tracer DiI. Our results indicate an increased spine density in both cortex and hippocampus in Fmr1 KO mice, which was not detected after LP-211 administration in both brain regions. Interestingly, the reduction of spine density in LP-211-treated Fmr1 KO mice affected thin spines. Our data suggest that in vivo administration of a selective agonist of 5-HT7 receptors results in the correction of increased spine density, a hallmark feature of FXS, suggesting that targeting of 5-HT7 receptors might be considered as a new therapeutic strategy for FXS.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
