Linking mitochondrial and synaptic weakness to schizophrenia

Schizophrenia (SZ) is a heterogenous neurodevelopmental disorder in which the complex and interacting
influences of genetics and environment drive neuropathological processes leading to symptom development.
While the precise neuropathological underpinnings of SZ remain undetermined, and multiple brain regions are
likely to be involved, both genetic and neuropathological evidence suggest that disrupted glutamatergic
synaptic function in the cerebral cortex can be an important component of symptom development in SZ.
Studies, including from the contact PI Stewart Anderson’s, lab have also suggested that mitochondrial
weakness may contribute to the development of schizophrenia. Since a major locus, perhaps the major locus,
of mitochondrial ATP dependence for neural function occurs in the presynaptic terminal, it stands to reason that
mitochondrial weakness could be one influencer of the glutamatergic synaptic disruption contributing to SZ.
The most common genetic risk factor for SZ is the 22q11.2 deletion syndrome (22qDS), occurring in about
1:3000 births, roughly one quarter of which develop SZ. We previously used IPSC-derived glutamatergic
neurons (iNeurons) and lymphoblastoid cell lines to demonstrate that while the condition of 22q+SZ is
associated with weaker ATP production via oxidative phosphorylation (OXPHOS), 22qDS without SZ
(22q(-)SZ) is associated with elevated levels of mitochondrial-biogenesis related transcripts that may denote a
compensatory mechanism reducing SZ risk. Treatment of iNeurons from the 22q+SZ group with the medication
bezafibrate resulted in enhanced expression of mitochondria biogenesis-related genes as well as normalization
of their ATP production. Here we propose to extend these studies with the following aims:
Aim 1: Study of mitochondrial biogenesis and mitophagy in IPSC-derived neurons from 22qDS with or without
SZ and unaffected controls. We hypothesize that there will be enhanced mitochondrial biogenesis and turnover
in the 22q(-)SZ group relative to both controls and 22q+SZ.
Aim 2: Study of glutamatergic synaptic release in IPSC-derived neurons from 22qDS with or without SZ and
unaffected controls. We hypothesize that OXPHOS deficits in IPSC-derived neurons from 22qDS+SZ will result
in reduced glutamatergic synaptic release and reduced synaptic vesicle cycling relative to neurons from 22qDS
without schizophrenia and to healthy controls, and that activation of mitochondrial biogenesis with bezafibrate
will normalize synaptic vesicle cycling and glutamate release in the 22qDS+SZ group.
Success in showing that 22q(-)SZ is associated with enhanced mitochondrial biogenesis/turnover would bolster
the rationale for targeting this system to prevent or ameliorate SZ symptoms in 22qDS. Since synaptic energetic
weakness, potentially interacting with genetic and environmental factors that also affect synaptic function, has
been implicated in non-syndromic SZ and other neuropsychiatric disorders, the novel human-based experimental
paradigms we apply in this proposal could be broadly applicable to other IPSC-based studies of brain disease.

Grant Number: 5R01MH136706-02
NIH Institute/Center: NIH
Principal Investigator: Stewart Anderson