Regionalized loss of parvalbumin interneurons in the cerebral cortex of mice with deficits in GFRalpha1 signaling.
Inhibitory interneurons are crucially important for cerebral cortex function and behavior. The mechanisms controlling inhibitory interneuron diversification and allocation to distinct cortical areas remain poorly understood. GDNF (glial cell line-derived neurotrophic factor) and its receptor GFRalpha1 have been implicated in the development of GABAergic precursors but, because of the early lethality of null mutants, their roles in postnatal maturation and function of cortical interneurons are unknown. "cis-only" mutant mice lack GFRalpha1 only in cells that do not express the RET signaling receptor subunit and survive to adulthood. At birth, both null mutants and cis-only mice showed a specific loss of GABAergic interneurons in rostro- and caudolateral cortical regions but not in more medial areas. Unexpectedly, the adult cortex of cis-only mice displayed a complete loss of parvalbumin (PV)-expressing GABAergic interneurons in discrete regions (PV holes) interspersed among areas of normal PV cell density. PV holes predominantly occurred in the visual and frontal cortices, and their size could be affected by neuronal activity. Consistent with deficits in cortical inhibitory activity, these mice showed enhanced cortical excitability, increased sensitivity to epileptic seizure, and increased social behavior. We propose that GFRalpha1 signaling guides the development of a subset of PV-expressing GABAergic interneurons populating discrete regions of the cerebral cortex and may thus contribute to the diversification and allocation of specific cortical interneuron subtypes.
Canty
Alison J
AJ
Department of Neuroscience, Division of Molecular Neurobiology, Karolinska Institute, S-171 77 Stockholm, Sweden.
Dietze
Jule
J
Harvey
Michael
M
Enomoto
Hideki
H
Milbrandt
Jeffrey
J
Ibáñez
Carlos F
CF
D000200:Action Potentials / Q000235:genetics; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001931:Brain Mapping; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D002540:Cerebral Cortex / Q000166:cytology*; D004195:Disease Models, Animal; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000172:deficiency*; D005968:Glutamate Decarboxylase / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D018398:Homeodomain Proteins / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000235:genetics; D007395:Interneurons / Q000378:metabolism*; D060850:LIM-Homeodomain Proteins; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064231:Nestin; D009433:Neural Inhibition / Q000235:genetics; D010320:Parvalbumins / Q000378:metabolism*; D010433:Pentylenetetrazole; D012640:Seizures / Q000139:chemically induced / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D012919:Social Behavior; D014157:Transcription Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
C494988:Gfra1 protein, mouse; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D018398:Homeodomain Proteins; D007381:Intermediate Filament Proteins; C498504:LHX6 protein, mouse; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D010320:Parvalbumins; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D005680:gamma-Aminobutyric Acid; D053148:Caspase 3; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D010433:Pentylenetetrazole