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Age‐dependent loss of parvalbumin‐expressing hippocampal interneurons in mice deficient in CHL 1, a mental retardation and schizophrenia susceptibility gene
Author(s) -
Schmalbach Barbara,
Lepsveridze Eka,
Djogo Nevena,
Papashvili Giorgi,
Kuang Fang,
Leshchyns'ka Iryna,
Sytnyk Vladimir,
Nikonenko Alexander G.,
Dityatev Alexander,
Jakovcevski Igor,
Schachner Melitta
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13284
Subject(s) - parvalbumin , hippocampal formation , excitatory postsynaptic potential , neuroscience , biology , inhibitory postsynaptic potential , synaptic plasticity , interneuron , hippocampus , long term potentiation , schizophrenia (object oriented programming) , endocrinology , psychology , receptor , genetics , psychiatry
In humans, deletions/mutations in the CHL 1/ CALL gene are associated with mental retardation and schizophrenia. Juvenile CHL 1‐deficient ( CHL 1 −/− ) 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 CHL 1 −/− mouse are affected during brain maturation and in adulthood. We found that hippocampal, but not neocortical, PV + interneurons were reduced with age in CHL 1 −/− 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 CA 1 pyramidal cells was reduced and a deficit in short‐ and long‐term potentiation developed at CA 3– CA 1 excitatory synapses between 2 and 9 months of age in CHL 1 −/− mice. This deficit could be abrogated by a GABA A receptor agonist. We propose that region‐specific aberrant GABA ergic 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.