Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice
Tomonori Kaifu, … , Hiroaki Asou, Toshiyuki Takai
Tomonori Kaifu, … , Hiroaki Asou, Toshiyuki Takai
Published February 1, 2003
Citation Information: J Clin Invest. 2003;111(3):323-332. https://doi.org/10.1172/JCI16923.
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Article Neuroscience

Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice

Abstract

Deletions in the DAP12 gene in humans result in Nasu-Hakola disease, characterized by a combination of bone fractures and psychotic symptoms similar to schizophrenia, rapidly progressing to presenile dementia. However, it is not known why these disorders develop upon deficiency in DAP12, an immunoreceptor signal activator protein initially identified in the immune system. Here we show that DAP12-deficient (DAP12–/–) mice develop an increased bone mass (osteopetrosis) and a reduction of myelin (hypomyelinosis) accentuated in the thalamus. In vitro osteoclast induction from DAP12–/– bone marrow cells yielded immature cells with attenuated bone resorption activity. Moreover, immature oligodendrocytes were arrested in the vicinity of the thalamus, suggesting that the primary defects in DAP12–/– mice are the developmental arrest of osteoclasts and oligodendrocytes. In addition, the mutant mice also showed synaptic degeneration, impaired prepulse inhibition, which is commonly observed in several neuropsychiatric diseases in humans including schizophrenia, and aberrant electrophysiological profiles in the thalami. These results provide a molecular basis for a unique combination of skeletal and psychotic characteristics of Nasu-Hakola disease as well as for schizophrenia and presenile dementia.

Authors

Tomonori Kaifu, Jin Nakahara, Masanori Inui, Kenichi Mishima, Toshihiko Momiyama, Mitsuji Kaji, Akiko Sugahara, Hisami Koito, Azusa Ujike-Asai, Akira Nakamura, Kiyoshi Kanazawa, Kyoko Tan-Takeuchi, Katsunori Iwasaki, Wayne M. Yokoyama, Akira Kudo, Michihiro Fujiwara, Hiroaki Asou, Toshiyuki Takai

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Figure 6

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Reduced startle response, impaired sensorimotor gating, and aberrant GAB...
Reduced startle response, impaired sensorimotor gating, and aberrant GABAergic mIPSC’s in DAP12–/– mice. (a) DAP12–/– mice (white bars) displayed significantly lower startle responses than did wild-type mice (black bars). F(1, 18) = 5.790, P < 0.05. The average startle responses at 100 and 110 dB were significantly lower in knockout mice. (b) DAP12–/– mice (white bars) displayed significantly lower prepulse (pp) inhibition than did wild-type mice (black bars). F(1, 18) = 5.061, P < 0.05. This effect was attributable to the acoustic startle pulse (p) stimulus of 100 dB. In a and b, the data are presented as mean ± SEM (n = 10, *P < 0.05). (c) Schematic illustration of a neural circuit for negative feedback giving rise to prepulse inhibition. The thalamus receives inhibition by GABAergic neurons. (d) Developmental change in the decay time constant of spontaneous mIPSC’s recorded from laterodorsal thalamic neurons in the presence of tetrodotoxin; 6-cyano-7-nitroquinoxaline-2,3-dione; D(−)-2-amino-5-phosphonopentanoic acid; and strychnine. The mean decay time constants of mIPSC’s recorded from DAP12–/– mice (open circles) were 12.2 ± 0.7 ms (n = 5) and 10.9 ± 0.2 ms (n = 4) at P20 and P62, respectively, whereas those from wild-type mice (filled circles) were 17.3 ± 1.1 ms (n = 4) and 8.1 ± 1.0 ms (n = 4) at P19 and P64, respectively. The numbers of neurons tested are given in parentheses. The decay time matched a monoexponential time course. The current traces on the left are the averaged mIPSC’s (from 491–999 events) at each age of wild-type or DAP12–/– mice.