Nature最新论文：Modelling schizophrenia using human induced pluripotent stemcell

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Schizophrenia (SCZD) is a debilitating neurological disorder with a
- [2 _7 U0 M! tworld-wide prevalence of 1%; there is a strong genetic component,
5 [5 ], ^2 h1 s- Uwith an estimated heritability of 80–85% 1 . Although post-mortem- ]3 F  r) O3 i" ]- G
studies have revealed reduced brain volume, cell size, spine density5 Q! A" P+ ~( l4 Z# E( Q2 @
and abnormal neural distribution in the prefrontal cortex and9 z/ A4 `# Y3 V0 L1 v- k
hippocampus of SCZD brain tissue 2 and neuropharmacological
  }& V1 F" f# U9 mstudies have implicated dopaminergic, glutamatergic and GABAergic
+ z, g, Y$ G4 Wactivity in SCZD 3 , the cell types affected in SCZD and the molecular
# ], `$ x  l# {% F3 p& [; ymechanisms underlying the disease state remain unclear. To elu-
! R- I# E# f( {cidate the cellular and molecular defects of SCZD, we directly repro-5 ^, e9 z& Y8 D  I2 d2 q: h
grammed fibroblasts from SCZD patients into human induced9 x: u7 c: L4 d  H. p! o0 T: o* o) d$ Z
pluripotent stem cells (hiPSCs) and  subsequently  differentiated$ I. e7 U  x& `3 \. z1 S
these disorder-specific hiPSCs into neurons (Supplementary Fig. 1).0 d- Q6 w; I  w$ }
SCZD hiPSC neurons showed diminished neuronal connectivity in
. t/ ^" F2 u  P  `6 |8 Qconjunction with decreased neurite number, PSD95-protein levels1 n2 f- }) N! r" y6 G, Q, u
and  glutamate  receptor  expression.  Gene  expression  profiles  of
8 R) [1 U( z1 w  n5 BSCZD hiPSC neurons identified altered expression of many compo-6 F! f) `' n: X* T9 l9 y! }' [
nents of the cyclic AMP and WNT signalling pathways. Key cellular
6 [1 A5 `% [% Y5 G& S  C) vand molecular elements of the SCZD phenotype were ameliorated
5 v! c: L  a/ a. |) f- C! rfollowing treatment of SCZD hiPSC neurons with the antipsychotic8 M0 L; C8 Z$ N5 q; f5 H' L# o
loxapine. To date, hiPSC neuronal pathology has only been demon-4 }! L4 Q; n% @1 |/ [) w1 M: P( Y
strated in diseases characterized by both the loss of function of a single
- ^4 p! P0 q4 {# ]) N* ygene product and rapid disease progression in early childhood 4–6 . We: Z6 D' s# F; Q4 \: F
now report hiPSC neuronal phenotypes and gene expression changes
" c! \: |2 K& _* w& T3 Q2 d) H; a, {associated with SCZD, a complex genetic psychiatric disorder.

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