ABSTRACT
Fibroblast growth factors (Fgfs) and their receptors (Fgfr) are expressed in the developing and adult CNS. Previous studies demonstrated a decrease in cortical interneurons and locomotor hyperactivity in mice with a conditional Fgfr1 deletion generated in radial glial cells during midneurogenesis (Fgfr1(f/f);hGfapCre+). Here, we report earlier and more extensive inactivation of Fgfr1 in neuroepithelial cells of the CNS (Fgfr1(f/f);NesCre+). Similar to findings in Fgfr1(f/f);hGfapCre+ mice, parvalbumin positive (PV+) cortical interneurons are also decreased in the neocortex of Fgfr1(f/f);NesCre+ mice when compared to control littermates (Fgfr1(f/f)). Fgfr1(f/f);NesCre+ embryos do not differ from controls in the initial specification of GABAergic cells in the ganglionic eminence (GE) as assessed by in situ hybridization for Dlx2, Mash1 and Nkx2. Equal numbers of GABAergic neuron precursors genetically labeled with green fluorescent protein (GFP) were observed at P0 in Fgfr1(f/f);hGfapCre+;Gad1-GFP mutant mice. However, fewer GFP+ and GFP+/PV+ interneurons were observed in these mutants at adulthood, indicating that a decrease in cortical interneuron markers is occurring postnatally. Fgfr1 is expressed in cortical astrocytes in the postnatal brain. To test whether the astrocytes of mice lacking Fgfr1 are less capable of supporting interneurons, we co-cultured wild type Gad1-GFP+ interneuron precursors isolated from the medial GE (MGE) with astrocytes from Fgfr1(f/f) control or Fgfr1(f/f);hGfapCre+ mice. Interneurons grown on Fgfr1 deficient astrocytes had small soma size and fewer neurites per cell, but no differences in cell survival. Decreased soma size of Gad67 immunopositive interneurons was also observed in the cortex of adult Fgfr1(f/f);NesCre+ mice. Our data indicate that astrocytes from Fgfr1 mutants are impaired in supporting the maturation of cortical GABAergic neurons in the postnatal period. This model may elucidate potential mechanisms of impaired PV interneuron maturation relevant to neuropsychiatric disorders that develop in childhood and adolescence.
Subject(s)
Gene Silencing , Interneurons/metabolism , Parvalbumins/metabolism , Receptor, Fibroblast Growth Factor, Type 1/genetics , Telencephalon/metabolism , Animals , Apoptosis/genetics , Astrocytes/metabolism , Cell Communication , Cell Count , Cell Movement/genetics , Cell Proliferation , Coculture Techniques , Gene Deletion , Gene Expression , Mice , Mice, Transgenic , Mutation , Parvalbumins/geneticsABSTRACT
BACKGROUND: Motor hyperactivity due to hyper-dopaminergic neurotransmission in the basal ganglia is well characterized; much less is known about the role of the neocortex in controlling motor behavior. METHODS: Locomotor behavior and motor, associative, and spatial learning were examined in mice with conditional null mutations of fibroblast growth factor receptor 1 (Fgfr1) restricted to telencephalic neural precursors (Fgfr1(f/f;hGfapCre)). Locomotor responses to a dopamine agonist (Amphetamine 2 mg/kg and Methylphenidate 10 mg/kg) and antagonists (SCH233390 .025 mg/kg and Haloperidol .2 mg/kg) were assessed. Stereological and morphological characterization of various monoaminergic, excitatory, and inhibitory neuronal subtypes was performed. RESULTS: Fgfr1(f/f;hGfapCre) mice have spontaneous locomotor hyperactivity characterized by longer bouts of locomotion and fewer resting points that is significantly reduced by the D1 and D2 receptor antagonists. No differences in dopamine transporter, tyrosine hydroxylase, or serotonin immunostaining were observed in Fgfr1(f/f;hGfapCre) mice. There was no change in cortical pyramidal neurons, but parvalbumin+, somatostatin+, and calbindin+ inhibitory interneurons were reduced in number in the cerebral cortex. The decrease in parvalbumin+ interneurons in cortex correlated with the extent of hyperactivity. CONCLUSIONS: Dysfunction in specific inhibitory cortical circuits might account for deficits in behavioral control, providing insights into the neurobiology of psychiatric disorders.
Subject(s)
Cerebral Cortex/pathology , Fibroblast Growth Factor 1/genetics , Hyperkinesis/genetics , Hyperkinesis/pathology , Neural Inhibition/genetics , Neurons/pathology , Amphetamine/therapeutic use , Animals , Behavior, Animal/drug effects , Biogenic Monoamines/metabolism , Cell Count/methods , Central Nervous System Stimulants/therapeutic use , Disease Models, Animal , Dopamine Agents/administration & dosage , Exploratory Behavior/drug effects , Fibroblast Growth Factor 1/deficiency , Glutamate Decarboxylase/metabolism , Hyperkinesis/drug therapy , Locomotion/drug effects , Locomotion/genetics , Male , Methylphenidate/therapeutic use , Mice , Mice, Knockout , Motor Activity/drug effects , Motor Activity/genetics , Nerve Tissue Proteins/metabolism , Signal Transduction/drug effects , Signal Transduction/geneticsABSTRACT
Midline astroglia in the cerebral cortex develop earlier than other astrocytes through mechanisms that are still unknown. We show that radial glia in dorsomedial cortex retract their apical endfeet at midneurogenesis and translocate to the overlaying pia, forming the indusium griseum. These cells require the fibroblast growth factor receptor 1 (Fgfr1) gene for their precocious somal translocation to the dorsal midline, as demonstrated by inactivating the Fgfr1 gene in radial glial cells and by RNAi knockdown of Fgfr1 in vivo. Dysfunctional astroglial migration underlies the callosal dysgenesis in conditional Fgfr1 knockout mice, suggesting that precise targeting of astroglia to the cortex has unexpected roles in axon guidance. FGF signaling is sufficient to induce somal translocation of radial glial cells throughout the cortex; furthermore, the targeting of astroglia to dorsolateral cortex requires FGFr2 signaling after neurogenesis. Hence, FGFs have an important role in the transition from radial glia to astrocytes by stimulating somal translocation of radial glial cells.
Subject(s)
Cell Movement/physiology , Cerebral Cortex/embryology , Corpus Callosum/embryology , Fibroblast Growth Factors/metabolism , Growth Cones/metabolism , Neuroglia/metabolism , Animals , Astrocytes/cytology , Astrocytes/metabolism , Cell Shape/genetics , Cerebral Cortex/cytology , Cerebral Cortex/metabolism , Corpus Callosum/cytology , Corpus Callosum/metabolism , Down-Regulation/genetics , Female , Fibroblast Growth Factor 8/metabolism , Growth Cones/ultrastructure , Male , Mice , Mice, Knockout , Mice, Transgenic , Neuroglia/cytology , RNA Interference , Receptor, Fibroblast Growth Factor, Type 1/genetics , Receptor, Fibroblast Growth Factor, Type 2/genetics , Receptor, Fibroblast Growth Factor, Type 2/metabolism , Signal Transduction/physiologyABSTRACT
BACKGROUND: The combination of the antidepressant fluoxetine (FLX) and the atypical antipsychotic olanzapine (OLA) appears to be more effective for the treatment of resistant depression than single drugs. We hypothesize that such combination may determine a specific modulation of neuroplastic genes, which could contribute to therapeutic activity. METHODS: We investigated the expression of the neurotrophic molecule basic fibroblast growth factor 2 (FGF-2) after acute or chronic administration of FLX and OLA, alone or in combination. Ribonuclease (RNase) protection assay and Western blot analysis were employed to determine FGF-2 expression in different brain structures and to identify the intracellular pathways possibly involved in FGF-2 modulation. RESULTS: After single injection, we found that FGF-2 mRNA levels were selectively upregulated in the prefrontal cortex only when the two drugs were coadministered, an effect paralleled by a significant increase of phosphorylated protein kinase B (P-Akt) levels. Conversely, chronic treatment with a combination of FLX and OLA (FLX+OLA) increased FGF-2 mRNA levels in prefrontal cortex, as well as in hippocampus and striatum. CONCLUSIONS: Based on these data, we hypothesize a role of endogenously synthesized FGF-2 in the effects of FLX/OLA combination on brain function and plasticity, which could contribute to its superior efficacy for the treatment of resistant depression.
Subject(s)
Benzodiazepines/administration & dosage , Brain/drug effects , Fibroblast Growth Factor 2/metabolism , Fluoxetine/administration & dosage , Gene Expression Regulation/drug effects , Protein Serine-Threonine Kinases , Selective Serotonin Reuptake Inhibitors/administration & dosage , Analysis of Variance , Animals , Benzodiazepines/pharmacology , Blotting, Western/methods , Brain/metabolism , Cyclic AMP Response Element-Binding Protein/metabolism , Drug Administration Schedule , Drug Combinations , Drug Synergism , Electrophoretic Mobility Shift Assay/methods , Fibroblast Growth Factor 2/genetics , Fluoxetine/pharmacology , Male , Olanzapine , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-akt , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Selective Serotonin Reuptake Inhibitors/pharmacology , Time FactorsABSTRACT
We have investigated the role of dopaminergic receptors in modulation of basic fibroblast growth factor (FGF-2) expression in rat prefrontal cortex and hippocampus, two brain regions important for cognition. We found that FGF-2 expression is upregulated by quinpirole, a D2 agonist, in prefrontal cortex and to a lesser extent in hippocampus. This modulation was specific for dopamine D2 receptors because no effect was observed when the dopamine D1 and D3 agonists, SKF38393 and 7-OH-DPAT, respectively, were administered. Our findings show that activation of dopaminergic D2 receptors modulates FGF-2 expression in rat prefrontal cortex and hippocampus. Our data highlight the complex modulation of FGF-2 expression in limbic areas pointing to this trophic molecule as a putative target of drugs used against acute and chronic neurodegenerative diseases such as Parkinson's disease.
