Inhibitory Interneuron Progenitor Transplantation Restores Normal Learning and Memory in ApoE4 Knock-In Mice without or with Aβ Accumulation

Tong, Leslie M.; Djukic, Biljana; Arnold, Christine; Gillespie, Anna K.; Yoon, Seo Yeon; Wang, Max; Zhang, Olivia; Knöferle, Johanna; Rubenstein, John L.R.; Alvarez-Buylla, Arturo; Huang, Yadong

doi:10.1523/jneurosci.0693-14.2014

Cited by 110 publications

(117 citation statements)

References 42 publications

(4 reference statements)

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“…by previous study showing that manipulation of the GABAergic/inhibitory system can rescue LTP and memory deficiency in APP/PS1 mouse model (Meilandt et al 2008, Yoshiike et al 2008, Andrews-Zwilling et al 2010, Tong et al 2014. Our results confirm this finding, and in addition show that the involvement of the GABAergic system is restricted to a later point in the pathological progression of the disease (i.e.…”

Section: Discussionsupporting

confidence: 91%

Age‑dependent concomitant changes in synaptic function and GABAergic pathway in the APP/PS1 mouse model

Tutu¹,

Bondt²,

Wyngaert³

et al. 2016

Acta Neurobiologiae Experimentalis

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Synaptic dysfunction is a well-documented manifestation in animal models of Alzheimer's disease pathology. In this context, numerous studies have documented reduction in the functionality of synapses in various models. In addition, recent research has shed more light on increased excitability and its link to seizures and seizure-like activities in AD patients as well as in mouse models. These reports of hyperexcitability contradict the observed reduction in synaptic function and have been suggested to be as a result of the interplay between inhibitory and excitatory neuronal mechanism. The present study therefore investigates functional deficiency in the inhibitory system as complementary to the identified alterations in the glutamate excitatory pathway in AD. Since synaptic function deficit in AD is typically linked to progression/pathology of the disease, it is important to determine whether the deficits in the GABAergic system are functional and can be directly linked to the pattern of the disruption documented in the glutamate system. To build on previous research in this field, experiments were designed to determine if previously documented synaptic dysfunction in AD models is concomitantly observed with excitation/inhibition imbalance as suggested by observation of seizure and seizure-like pathology in such models. We report changes in synaptic function in aged APPPS1 mice not observable in the younger cohort. These changes in synaptic function are furthermore accompanied by alteration in the GABAergic neurotransmission. Thus, age-dependent alteration in the inhibitory/ excitatory balance might underpin the symptomatic changes observed with the progression of Alzheimer's disease pathology including sleep disturbance and epileptic events.

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Section: Discussionsupporting

confidence: 91%

Age‑dependent concomitant changes in synaptic function and GABAergic pathway in the APP/PS1 mouse model

Tutu¹,

Bondt²,

Wyngaert³

et al. 2016

Acta Neurobiologiae Experimentalis

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“…Loss of GABAergic terminals has been reported in human AD brain (141), network imbalance in the hAPPJ20 transgenic model of AD has been linked to reduced GABAergic activity (142) and transplantation of GABAergic interneurons restores AD related cognitive decline in mice (143). The strongest evidence for a role of astrocytes has come from research by Wu et al,…”

Section: Slc6 Neurotransmitter Transportersmentioning

confidence: 99%

Astrocytic transporters in Alzheimer's disease

Ugbode

Whalley

et al. 2017

Biochemical Journal

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Astrocytes play a fundamental role in maintaining the health and function of the central nervous system. Increasing evidence indicates that astrocytes undergo both cellular and molecular changes at an early stage in neurological diseases, including Alzheimer's disease (AD). These changes may reflect a change from a neuroprotective to a neurotoxic phenotype. Given the lack of current disease-modifying therapies for AD, astrocytes have become an interesting and viable target for therapeutic intervention. The astrocyte transport system covers a diverse array of proteins involved in metabolic support, neurotransmission and synaptic architecture. Therefore, specific targeting of individual transporter families has the potential to suppress neurodegeneration, a characteristic hallmark of AD. A small number of the 400 transporter superfamilies are expressed in astrocytes, with evidence highlighting a fraction of these are implicated in AD. Here, we review the current evidence for six astrocytic transporter subfamilies involved in AD, as reported in both animal and human studies. This review confirms that astrocytes are indeed a viable target, highlights the complexities of studying astrocytes and provides future directives to exploit the potential of astrocytes in tackling AD.

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“…However, a recent study has investigated the effects of replacing lost or impaired GABA-ergic interneurons on neuronal signaling and behavioral deficits in an AD model (Tong et al, 2014, Table 3). In this study, freshly dissected E13.5 mouse MGE progenitors were grafted bilaterally into the dentate hilus of 14 months old female apoE4 knock-in mice displaying substantial hilar GABA-ergic inter- Furthermore, MGE cell grafting prevented apoE4-induced memory deficits in a probe trial of the water maze test, corrected the abnormal activity, anxiety, and exploratory behaviors in open field and elevated plus maze tests (Tong et al, 2014). Thus, grafting of inhibitory interneurons was found efficacious for restoring normal cognitive function in an AD model, which highlights the role of interneuron dysfunction in AD pathogenesis and the promise of cell replacement therapy for improving cognitive function in AD, particularly when intervened in early stages of the disease.…”

Section: Promise Of Gaba-ergic Cell Therapy For Alzheimer's Diseasementioning

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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Inhibitory Interneuron Progenitor Transplantation Restores Normal Learning and Memory in ApoE4 Knock-In Mice without or with Aβ Accumulation

Cited by 110 publications

References 42 publications

Age‑dependent concomitant changes in synaptic function and GABAergic pathway in the APP/PS1 mouse model

Age‑dependent concomitant changes in synaptic function and GABAergic pathway in the APP/PS1 mouse model

Astrocytic transporters in Alzheimer's disease

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

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