Hippocampal hyperexcitability underlies enhanced fear memories in TgNTRK3, a panic disorder mouse model.
Panic attacks are a hallmark in panic disorder (PAND). During the panic attack, a strong association with the surrounding context is established suggesting that the hippocampus may be critically involved in the pathophysiology of PAND, given its role in contextual processing. We previously showed that variation in the expression of the neurotrophin tyrosine kinase receptor type 3 (NTRK3) in both PAND patients and a transgenic mouse model (TgNTRK3) may have a role in PAND pathophysiology. Our study examines hippocampal function and activation of the brain fear network in TgNTRK3 mice. TgNTRK3 mice showed increased fear memories accompanied by impaired extinction, congruent with an altered activation pattern of the amygdala-hippocampus-medial prefrontal cortex fear circuit. Moreover, TgNTRK3 mice also showed an unbalanced excitation-to-inhibition ratio in the hippocampal cornu ammonis 3 (CA3)-CA1 subcircuit toward hyperexcitability. The resulting hippocampal hyperexcitability underlies the enhanced fear memories, as supported by the efficacy of tiagabine, a GABA reuptake inhibitor, to rescue fear response. The fearful phenotype appears to be the result of hippocampal hyperexcitability and aberrant fear circuit activation. We conclude that NTRK3 plays a role in PAND by regulating hippocampus-dependent fear memories.
Systems Biology Programme, Centre for Genomic Regulation, E-08003 Barcelona, Spain, Universitat Pompeu Fabra, E-08003 Barcelona, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras, E-08003 Barcelona, Spain, Department of Stem Cells and Regeneration, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, and Institute of Biology, Otto-von-Guericke University Magdeburg, and Center for Behavioral Brain Sciences, D39120 Magdeburg, Germany.
Mónica
M
Santos
Davide
D
D'Amico
Ornella
O
Spadoni
Alejandro
A
Amador-Arjona
Oliver
O
Stork
Mara
M
Dierssen
D000704:Analysis of Variance; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology; D005239:Fear; D018755:GABA Agonists / Q000494:pharmacology; D005793:Generalization, Psychological / Q000187:drug effects / Q000502:physiology; D005968:Glutamate Decarboxylase / Q000378:metabolism; D051528:Guanylate Kinases / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D008164:Luminescent Proteins / Q000235:genetics; D018782:Maze Learning / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009557:Nipecotic Acids / Q000494:pharmacology; D016584:Panic Disorder / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D010880:Piperidines / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D020812:Receptor, trkC / Q000235:genetics*; D000078308:Tiagabine; D050496:Vesicular Glutamate Transport Proteins / Q000378:metabolism
D001426:Bacterial Proteins; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D008164:Luminescent Proteins; D008565:Membrane Proteins; D009557:Nipecotic Acids; D010880:Piperidines; D016760:Proto-Oncogene Proteins c-fos; D050496:Vesicular Glutamate Transport Proteins; C054562:yellow fluorescent protein, Bacteria; D020812:Receptor, trkC; D051528:Guanylate Kinases; D005968:Glutamate Decarboxylase; C010739:ifenprodil; D000078308:Tiagabine