title: GABAergic terminals are a source of galanin to modulate cholinergic neuron development in the neonatal forebrain.
abstract: The distribution and (patho-)physiological role of neuropeptides in the adult and aging brain have been extensively studied. Galanin is an inhibitory neuropeptide that can coexist with γ-aminobutyric acid (GABA) in the adult forebrain. However, galanin's expression sites, mode of signaling, impact on neuronal morphology, and colocalization with amino acid neurotransmitters during brain development are less well understood. Here, we show that galaninergic innervation of cholinergic projection neurons, which preferentially express galanin receptor 2 (GalR2) in the neonatal mouse basal forebrain, develops by birth. Nerve growth factor (NGF), known to modulate cholinergic morphogenesis, increases GalR2 expression. GalR2 antagonism (M871) in neonates reduces the in vivo expression and axonal targeting of the vesicular acetylcholine transporter (VAChT), indispensable for cholinergic neurotransmission. During cholinergic neuritogenesis in vitro, GalR2 can recruit Rho-family GTPases to induce the extension of a VAChT-containing primary neurite, the prospective axon. In doing so, GalR2 signaling dose-dependently modulates directional filopodial growth and antagonizes NGF-induced growth cone differentiation. Galanin accumulates in GABA-containing nerve terminals in the neonatal basal forebrain, suggesting its contribution to activity-driven cholinergic development during the perinatal period. Overall, our data define the cellular specificity and molecular complexity of galanin action in the developing basal forebrain.
authors.affiliation: Department of Neuroscience, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm SE-17177, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Keimpema
authors.affiliation: Department of Neuroscience.
authors.forename: Kang
authors.initials: K
authors.lastname: Zheng
authors.affiliation: Department of Neuroscience.
authors.forename: Swapnali Shantaram
authors.initials: SS
authors.lastname: Barde
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm SE-17177, Sweden.
authors.forename: Paul
authors.initials: P
authors.lastname: Berghuis
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm SE-17177, Sweden.
authors.forename: Márton B
authors.initials: MB
authors.lastname: Dobszay
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm SE-17177, Sweden.
authors.forename: Robert
authors.initials: R
authors.lastname: Schnell
authors.affiliation: Department of Neuroscience, Science for Life Laboratory, Royal Institute of Technology, Stockholm SE-17121, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Mulder
authors.affiliation: Department of Molecular Neurobiology, University of Groningen, Groningen NL-9747 AG, The Netherlands.
authors.forename: Paul G M
authors.initials: PG
authors.lastname: Luiten
authors.affiliation: Department of Neuroscience, Beijing Institute for Neuroscience, Beijing Center for Neural Regeneration and Repairing, Department of Neurobiology, Capital Medical University, Beijing 100069, China.
authors.forename: Zhiqing David
authors.initials: ZD
authors.lastname: Xu
authors.affiliation: Department of Neurochemistry, Stockholm University, Stockholm SE-10691, Sweden and.
authors.forename: Johan
authors.initials: J
authors.lastname: Runesson
authors.affiliation: Department of Neurochemistry, Stockholm University, Stockholm SE-10691, Sweden and.
authors.forename: Ülo
authors.initials: Ü
authors.lastname: Langel
authors.affiliation: R&D China, GlaxoSmithKline, Pudong, Shanghai 201203, China.
authors.forename: Bai
authors.initials: B
authors.lastname: Lu
authors.affiliation: Department of Neuroscience.
authors.forename: Tomas
authors.initials: T
authors.lastname: Hökfelt
authors.affiliation: Department of Neuroscience, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm SE-17177, Sweden.
authors.forename: Tibor
authors.initials: T
authors.lastname: Harkany
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D059329:Cholinergic Neurons / Q000166:cytology* / Q000187:drug effects; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019004:Galanin / Q000378:metabolism* / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D005968:Glutamate Decarboxylase / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D020932:Nerve Growth Factor / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D016548:Prosencephalon / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D051381:Rats; D017208:Rats, Wistar; D017470:Receptors, Glutamate / Q000235:genetics / Q000378:metabolism; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D017470:Receptors, Glutamate; D050494:Vesicular Acetylcholine Transport Proteins; D005680:gamma-Aminobutyric Acid; D019004:Galanin; D020932:Nerve Growth Factor; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1
keywords: axon; basal forebrain; galanin receptor 2; neurotrophin; projection
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