Age-dependent loss of parvalbumin-expressing hippocampal interneurons in mice deficient in CHL1, a mental retardation and schizophrenia susceptibility gene.
In humans, deletions/mutations in the CHL1/CALL gene are associated with mental retardation and schizophrenia. Juvenile CHL1-deficient (CHL1(-/-) ) mice have been shown to display abnormally high numbers of parvalbumin-expressing (PV(+) ) hippocampal interneurons and, as adults, display behavioral traits observed in neuropsychiatric disorders. Here, we addressed the question whether inhibitory interneurons and synaptic plasticity in the CHL1(-/-) mouse are affected during brain maturation and in adulthood. We found that hippocampal, but not neocortical, PV(+) interneurons were reduced with age in CHL1(-/-) mice, from a surplus of +27% at 1 month to a deficit of -20% in adulthood compared with wild-type littermates. This loss occurred during brain maturation, correlating with microgliosis and enhanced interleukin-6 expression. In parallel with the loss of PV(+) interneurons, the inhibitory input to adult CA1 pyramidal cells was reduced and a deficit in short- and long-term potentiation developed at CA3-CA1 excitatory synapses between 2 and 9 months of age in CHL1(-/-) mice. This deficit could be abrogated by a GABAA receptor agonist. We propose that region-specific aberrant GABAergic synaptic connectivity resulting from the mutation and a subsequently enhanced synaptic elimination during brain maturation lead to microgliosis, increase in pro-inflammatory cytokine levels, loss of interneurons, and impaired synaptic plasticity. Close homolog of L1-deficient (CHL1(-/-) ) mice have abnormally high numbers of parvalbumin (PV)-expressing hippocampal interneurons in juvenile animals, but in adult animals a loss of these cells is observed. This loss correlates with an increased density of microglia (M), enhanced interleukin-6 (IL6) production and a deficit in short- and long-term potentiation at CA3-CA1 excitatory synapses. Furthermore, adult CHL1(-/-) mice display behavioral traits similar to those observed in neuropsychiatric disorders of humans.
Zentrum für Molekulare Neurobiologie, Universität Hamburg, Hamburg, Germany.
Barbara
B
Schmalbach
Zentrum für Molekulare Neurobiologie, Universität Hamburg, Hamburg, Germany.|Ilia State University, Tbilisi, Georgia.
Eka
E
Lepsveridze
Zentrum für Molekulare Neurobiologie, Universität Hamburg, Hamburg, Germany.
Nevena
N
Djogo
Zentrum für Molekulare Neurobiologie, Universität Hamburg, Hamburg, Germany.
Giorgi
G
Papashvili
Zentrum für Molekulare Neurobiologie, Universität Hamburg, Hamburg, Germany.
Fang
F
Kuang
Zentrum für Molekulare Neurobiologie, Universität Hamburg, Hamburg, Germany.|School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW, Australia.
Iryna
I
Leshchyns'ka
Zentrum für Molekulare Neurobiologie, Universität Hamburg, Hamburg, Germany.|School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW, Australia.
Vladimir
V
Sytnyk
Zentrum für Molekulare Neurobiologie, Universität Hamburg, Hamburg, Germany.|Department of Cytology, Bogomoletz Institute of Physiology, Kiev, Ukraine.
Alexander G
AG
Nikonenko
Zentrum für Molekulare Neurobiologie, Universität Hamburg, Hamburg, Germany.|Deutsches Zentrum für Neurodegenerative Erkrankungen, Magdeburg, Germany.
Alexander
A
Dityatev
Zentrum für Molekulare Neurobiologie, Universität Hamburg, Hamburg, Germany.|Experimental Neurophysiology, University Hospital Cologne, Köln, Germany.|German Center for Neurodegenerative Diseases, Bonn, Germany.
Igor
I
Jakovcevski
Zentrum für Molekulare Neurobiologie, Universität Hamburg, Hamburg, Germany.|Department of Cell Biology and Neuroscience, Keck Center for Collaborative Neuroscience, Rutgers University, Piscataway, New Jersey, USA.|Center for Neuroscience, Shantou University Medical College, Shantou, China.
Melitta
M
Schachner
D000375:Aging; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000172:deficiency* / Q000235:genetics; D002531:Cerebellum; D004797:Enzyme-Linked Immunosorbent Assay; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D006624:Hippocampus / Q000166:cytology*; D066298:In Vitro Techniques; D007377:Interleukin-3 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007395:Interneurons / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D008854:Microscopy, Electron; D010320:Parvalbumins / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D009418:S100 Proteins / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure
C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules; C490649:Chl1 protein, mouse; D007377:Interleukin-3; D015850:Interleukin-6; D008840:Microfilament Proteins; D010320:Parvalbumins; D009418:S100 Proteins; D010751:Phosphopyruvate Hydratase
close homolog of L1; hippocampus; interneu- rons; long-term potentiation; parvalbumin; synaptic plasticity