Knockdown of DISC1 by In Utero Gene Transfer Disturbs Postnatal Dopaminergic Maturation in the Frontal Cortex and Leads to Adult Behavioral Deficits

Niwa, Minae; Kamiya, Atsushi; Murai, Rina; Kubo, Ken Ichiro; Gruber, Aaron J.; Tomita, Kenji; Lu, Lingling; Tomisato, Shuta; Jaaro-Peled, Hanna; Seshadri, Saurav; Hiyama, Hideki; Huang, Beverly; Kohda, Kazuhisa; Noda, Yukihiro; O’Donnell, Patricio; Nakajima, Kazunori; Sawa, Akira; Nabeshima, Toshitaka

doi:10.1016/j.neuron.2010.01.019

Cited by 278 publications

(300 citation statements)

References 55 publications

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“…We then investigated whether transplantation prevented the PCP-induced cognitive deficits by measuring the cognitive function of mice with the NORT (Ennaceur and Delacour, 1988;Tang et al, 1999;Niwa et al, 2010). The mice were exposed to two objects during the training session, and 1 d later they were tested for their ability to discriminate between a familiar object and a novel object during a retention session in which one of the two objects used in the training session had been replaced by a novel object (see Materials and Methods).…”

Section: Resultsmentioning

confidence: 99%

GABAergic Precursor Transplantation into the Prefrontal Cortex Prevents Phencyclidine-Induced Cognitive Deficits

Tanaka

Toriumi

Kubo³

et al. 2011

J. Neurosci.

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Phencyclidine (PCP) is a noncompetitive NMDA receptor antagonist, and it induces schizophreniform cognitive deficits in healthy humans and similar cognitive deficits in rodents. Although the PCP-induced cognitive deficits appear to be accompanied and possibly caused by dysfunction of GABAergic inhibitory interneurons in the prefrontal cortex (PFC), the potential benefit(s) of GABAergic interneuron manipulations on PCP-induced cognitive deficits remains unexplored. In this study we show that when embryonic medial ganglionic eminence (MGE) cells, many of which differentiate into cortical GABAergic interneurons in situ, were grafted into the medial PFC (mPFC) of neonatal mice, they differentiated into a specific class of GABAergic interneurons and became functionally integrated into the host neuronal circuitry in adults. Prior MGE cell transplantation into the mPFC significantly prevented the induction of cognitive and sensory-motor gating deficits by PCP. The preventive effects were not reproduced by either transplantation of cortical projection neuron precursors into the mPFC or transplantation of MGE cells into the occipital cortex. The preventive effects of MGE cell transplantation into the mPFC were accompanied by activation of callosal projection neurons in the mPFC. These findings suggest that increasing GABAergic interneuron precursors in the PFC may contribute to the development of a cell-based approach as a novel means of modulating the PFC neuronal circuitry and preventing schizophreniform cognitive deficits.

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Section: Resultsmentioning

confidence: 99%

GABAergic Precursor Transplantation into the Prefrontal Cortex Prevents Phencyclidine-Induced Cognitive Deficits

Tanaka

Toriumi

Kubo³

et al. 2011

J. Neurosci.

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“…Progenitor cells of layer 2/3 neurons in the SSC and AFC were transfected using in utero electroporation 63,64 . E15.5 timed pregnant mice were deeply anaesthetized with an intraperitoneal injection of pentobarbital (100 mg kg À 1 ) and the uterine horns were exposed.…”

Section: Methodsmentioning

confidence: 99%

Enhanced synapse remodelling as a common phenotype in mouse models of autism

et al. 2014

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Developmental deficits in neuronal connectivity are considered to be present in patients with autism spectrum disorders (ASDs). Here we examine this possibility by using in vivo spine imaging in the early postnatal cortex of ASD mouse models. Spines are classified by the presence of either the excitatory postsynaptic marker PSD-95 or the inhibitory postsynaptic marker gephyrin. ASD mouse models show consistent upregulation in the dynamics of PSD-95-positive spines, which may subsequently contribute to stable synaptic connectivity. In contrast, spines receiving inputs from the thalamus, detected by the presence of gephyrin clusters, are larger, highly stable and unaffected in ASD mouse models. Importantly, two distinct mouse models, human 15q11-13 duplication and neuroligin-3 R451C point mutation, show highly similar phenotypes in spine dynamics. This selective impairment in dynamics of PSD-95-positive spines receiving intracortical projections may be a core component of early pathological changes and be a potential target of early intervention.

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“…This procedure was performed according the published protocol with minor modifications (24,25). Briefly, pregnant C57BL/6 mice were anesthetized at embryonic day 14.5 (E14.5) by isoflurane, and shRNA plasmids (control or DISC1 shRNA) together with CAG::Venus vector were injected into the bilateral ventricles.…”

Section: Methodsmentioning

confidence: 99%

“…6A). In this model, by in utero electroporation, DISC1 shRNA is selectively targeted to the cells in a lineage of the pyramidal neurons in the layer II/III of the prefrontal cortex (24,25). Among the PAK inhibitors tested above, FRAX486 displayed the highest penetrance of blood-brain barrier (Fig.…”

Section: Pak Inhibitors Reverse Preexisting Dendritic Spine Shrinkagementioning

confidence: 99%

PAKs inhibitors ameliorate schizophrenia-associated dendritic spine deterioration in vitro and in vivo during late adolescence

Hayashi‐Takagi

Araki

Nakamura

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Drug discovery in psychiatry has been limited to chemical modifications of compounds originally discovered serendipitously. Therefore, more mechanism-oriented strategies of drug discovery for mental disorders are awaited. Schizophrenia is a devastating mental disorder with synaptic disconnectivity involved in its pathophysiology. Reduction in the dendritic spine density is a major alteration that has been reproducibly reported in the cerebral cortex of patients with schizophrenia. Disruptedin-Schizophrenia-1 (DISC1), a factor that influences endophenotypes underlying schizophrenia and several other neuropsychiatric disorders, has a regulatory role in the postsynaptic density in association with the NMDA-type glutamate receptor, Kalirin-7, and Rac1. Prolonged knockdown of DISC1 leads to synaptic deterioration, reminiscent of the synaptic pathology of schizophrenia. Thus, we tested the effects of novel inhibitors to p21-activated kinases (PAKs), major targets of Rac1, on synaptic deterioration elicited by knockdown expression of DISC1. These compounds not only significantly ameliorated the synaptic deterioration triggered by DISC1 knockdown but also partially reversed the size of deteriorated synapses in culture. One of these PAK inhibitors prevented progressive synaptic deterioration in adolescence as shown by in vivo two-photon imaging and ameliorated a behavioral deficit in prepulse inhibition in adulthood in a DISC1 knockdown mouse model. The efficacy of PAK inhibitors may have implications in drug discovery for schizophrenia and related neuropsychiatric disorders in general.mechanism-oriented drug discovery | synapse protection

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Knockdown of DISC1 by In Utero Gene Transfer Disturbs Postnatal Dopaminergic Maturation in the Frontal Cortex and Leads to Adult Behavioral Deficits

Cited by 278 publications

References 55 publications

GABAergic Precursor Transplantation into the Prefrontal Cortex Prevents Phencyclidine-Induced Cognitive Deficits

GABAergic Precursor Transplantation into the Prefrontal Cortex Prevents Phencyclidine-Induced Cognitive Deficits

Enhanced synapse remodelling as a common phenotype in mouse models of autism

PAKs inhibitors ameliorate schizophrenia-associated dendritic spine deterioration in vitro and in vivo during late adolescence

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