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

Tanaka, Daichi; Toriumi, Kazuya; Kubo, Ken Ichiro; Nabeshima, Toshitaka; Nakajima, Kazunori

doi:10.1523/jneurosci.2786-11.2011

Cited by 48 publications

(42 citation statements)

References 59 publications

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“…We hypothesize that the remarkable, sustained impact of the transplants observed here is related to the source and developmental stage of the transplanted cells: the ventral MGE at mouse embryonic day 15.5. Our findings extend previous studies showing that transplanted MGE-derived GABA neurons establish a high degree of synaptic connectivity and induce plasticity in the host cortex, and have procognitive effects in disease models (3,25,38,39). The impacts of the MGE transplants on DA system function observed here and in a recent report (36) further illustrate the potential of GABA interneuron precursor-rich transplants in experimental therapeutics in schizophrenia (3,6).…”

Section: Drug Groups Combined) (D) Average Post-amph Locomotion Issupporting

confidence: 88%

Interneuron precursor transplants in adult hippocampus reverse psychosis-relevant features in a mouse model of hippocampal disinhibition

Gilani

Chohan²,

Inan

et al. 2014

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

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GABAergic interneuron hypofunction is hypothesized to underlie hippocampal dysfunction in schizophrenia. Here, we use the cyclin D2 knockout (Ccnd2 −/− ) mouse model to test potential links between hippocampal interneuron deficits and psychosis-relevant neurobehavioral phenotypes. Ccnd2 −/− mice show cortical PV + interneuron reductions, prominently in hippocampus, associated with deficits in synaptic inhibition, increased in vivo spike activity of projection neurons, and increased in vivo basal metabolic activity (assessed with fMRI) in hippocampus. Ccnd2 −/− mice show several neurophysiological and behavioral phenotypes that would be predicted to be produced by hippocampal disinhibition, including increased ventral tegmental area dopamine neuron population activity, behavioral hyperresponsiveness to amphetamine, and impairments in hippocampus-dependent cognition. Remarkably, transplantation of cells from the embryonic medial ganglionic eminence (the major origin of cerebral cortical interneurons) into the adult Ccnd2 −/− caudoventral hippocampus reverses these psychosisrelevant phenotypes. Surviving neurons from these transplants are 97% GABAergic and widely distributed within the hippocampus. Up to 6 mo after the transplants, in vivo hippocampal metabolic activity is lowered, context-dependent learning and memory is improved, and dopamine neuron activity and the behavioral response to amphetamine are normalized. These findings establish functional links between hippocampal GABA interneuron deficits and psychosis-relevant dopaminergic and cognitive phenotypes, and support a rationale for targeting limbic cortical interneuron function in the prevention and treatment of schizophrenia.parvalbumin | temporal lobe-dependent cognition | neural stem cell therapy | functional magnetic resonance imaging | contextual fear conditioning P recursors of most γ-aminobutyric acid (GABA)-releasing interneurons of the cerebral cortex and the hippocampus originate in the embryonic medial ganglionic eminence (MGE) (1-3). A subpopulation of MGE-derived cells differentiates into fast-spiking, parvalbumin-expressing (PV +

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Section: Drug Groups Combined) (D) Average Post-amph Locomotion Issupporting

confidence: 88%

Interneuron precursor transplants in adult hippocampus reverse psychosis-relevant features in a mouse model of hippocampal disinhibition

Gilani

Chohan²,

Inan

et al. 2014

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

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Section: Gaba-ergic Cell Grafts For Treating Schizophreniamentioning

confidence: 99%

“…A cohort of newborn mice received E13.5 mouse MGE progenitor cell grafts into the medial prefrontal cortex and another cohort received vehicle into the same region (Tanaka et al, 2011, Table 1). Six weeks later, mice in both groups were treated with PCP, a noncompetitive NMDA receptor antagonist that induces schizophreniform cognitive deficits in healthy humans as well as in rodents (Tanaka et al, 2011). As expected, mice that received vehicle (sham-grafting surgery) into the medial prefrontal cortex in the neonatal period exhibited impaired performance in exploratory preference during the retention sessions of novel object recognition test (NORT), performed 30 min after PCP administration.…”

Section: Gaba-ergic Cell Grafts For Treating Schizophreniamentioning

confidence: 99%

Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer׳s and Parkinson׳s diseases

Shetty

Bates

2016

Brain Research

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Several neurological and psychiatric disorders present hyperexcitability of neurons in specific regions of the brain or spinal cord, partly because of some loss and/or dysfunction of gammaamino butyric acid positive (GABA-ergic) inhibitory interneurons. Strategies that enhance inhibitory neurotransmission in the affected brain regions may therefore ease several or most deficits linked to these disorders. This perception has incited a huge interest in testing the efficacy of GABA-ergic interneuron cell grafting into regions of the brain or spinal cord exhibiting hyperexcitability, dearth of GABA-ergic interneurons or impaired inhibitory neurotransmission, using preclinical models of neurological and psychiatric disorders. Interneuron progenitors from the embryonic ventral telencephalon capable of differentiating into diverse subclasses of interneurons have particularly received much consideration because of their ability for dispersion, migration and integration with the host neural circuitry after grafting. The goal of this review is to discuss the premise, scope and advancement of GABA-ergic cell therapy for easing neurological deficits in preclinical models of schizophrenia, chronic neuropathic pain, Alzheimer's disease and Parkinson's disease. As grafting studies in these prototypes have so far utilized either primary cells from the embryonic medial and lateral ganglionic eminences or neural progenitor cells expanded from these eminences as donor material, the proficiency of these cell types is highlighted. Moreover, future studies that are essential prior to considering the possible clinical application of these cells for the above neurological conditions are proposed. Particularly, the need for grafting studies utilizing medial ganglionic eminence-like progenitors generated from human pluripotent stem cells via directed differentiation approaches or somatic cells through direct reprogramming methods are emphasized.

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“…For instance, a substantial amelioration of symptoms was observed in models of epilepsy (Hunt et al 2013), Alzheimer's disease (Tong et al 2014), Parkinson's disease (Martinez-Cerdeno et al 2010), or schizophrenia (Tanaka et al 2011) (see Southwell et al 2014 for a recent review). Our results show that the transplantation of specific classes of interneurons is capable of rejuvenating the cortex even at an advanced age, and that, therefore, the capacity for substantial plasticity is preserved in the cortex throughout life.…”

Section: Resultsmentioning

confidence: 99%

Embryonic interneurons from the medial, but not the caudal ganglionic eminence trigger ocular dominance plasticity in adult mice

et al. 2016

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The maturation of cortical inhibition provided by parvalbumin-containing basket cells derived from the medial ganglionic eminence (MGE) is a key event in starting the enhanced visual cortical plasticity during the critical period. Although it is generally assumed that a further increase in inhibition closes the critical period again, it was recently shown that embryonic interneurons derived from the MGE can induce an additional, artificial critical period when injected into the visual cortex of young mice. It has, however, remained open whether this effect was indeed specific for MGE-derived cells, and whether critical period-like plasticity could also be induced in fully adult animals. To clarify these issues, we injected explants from either the MGE or the caudal ganglionic eminence (CGE) into the visual cortices of fully adult mice, and performed monocular deprivation 33 days later for 4 days. Animals implanted with MGE cells, but not with CGE cells, showed marked ocular dominance plasticity. Immunohistochemistry confirmed that the injected cells from both sources migrated far in the host cortex, that most developed into neurons producing GABA, and that only cells from the MGE expressed parvalbumin. Thus, our results confirm that the plasticity-inducing effect of embryonic interneurons is specific for cells from the MGE, and is independent of the host animal's age.

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

Cited by 48 publications

References 59 publications

Interneuron precursor transplants in adult hippocampus reverse psychosis-relevant features in a mouse model of hippocampal disinhibition

Interneuron precursor transplants in adult hippocampus reverse psychosis-relevant features in a mouse model of hippocampal disinhibition

Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer׳s and Parkinson׳s diseases

Embryonic interneurons from the medial, but not the caudal ganglionic eminence trigger ocular dominance plasticity in adult mice

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