Deficiency in inhibitory cortical interneurons associates with hyperactivity in fibroblast growth factor receptor 1 mutant mice.
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.
Müller Smith
Karen
K
Child Study Center, Yale University, New Haven, Connecticut 06520, USA.
Fagel
Devon M
DM
Stevens
Hanna E
HE
Rabenstein
Rebecca L
RL
Maragnoli
Maria Elisabetta
ME
Ohkubo
Yasushi
Y
Picciotto
Marina R
MR
Schwartz
Michael L
ML
Vaccarino
Flora M
FM
D000661:Amphetamine / Q000627:therapeutic use; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015306:Biogenic Monoamines / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D000697:Central Nervous System Stimulants / Q000627:therapeutic use; D002540:Cerebral Cortex / Q000473:pathology*; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000008:administration & dosage; D005106:Exploratory Behavior / Q000187:drug effects; D016220:Fibroblast Growth Factor 1 / Q000172:deficiency / Q000235:genetics*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006948:Hyperkinesis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D008297:Male; D008774:Methylphenidate / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009433:Neural Inhibition / Q000235:genetics*; D009474:Neurons / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D015306:Biogenic Monoamines; D000697:Central Nervous System Stimulants; D015259:Dopamine Agents; D009419:Nerve Tissue Proteins; D016220:Fibroblast Growth Factor 1; D008774:Methylphenidate; D000661:Amphetamine; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1