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Imbalance in the response of pre- and post-synaptic components to amyloidopathy.

ABSTRACT: Alzheimer's disease (AD)-associated synaptic dysfunction drives the progression of pathology from its earliest stages. Amyloid ? (A?) species, both soluble and in plaque deposits, have been causally related to the progressive, structural and functional impairments observed in AD. It is, however, still unclear how A? plaques develop over time and how they progressively affect local synapse density and turnover. Here we observed, in a mouse model of AD, that A? plaques grow faster in the earlier stages of the disease and if their initial area is >500?µm2; this may be due to deposition occurring in the outer regions of the plaque, the plaque cloud. In addition, synaptic turnover is higher in the presence of amyloid pathology and this is paralleled by a reduction in pre- but not post-synaptic densities. Plaque proximity does not appear to have an impact on synaptic dynamics. These observations indicate an imbalance in the response of the pre- and post-synaptic terminals and that therapeutics, alongside targeting the underlying pathology, need to address changes in synapse dynamics.

SUBMITTER: Stephen TL

PROVIDER: S-EPMC6795896 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Imbalance in the response of pre- and post-synaptic components to amyloidopathy.

Stephen Terri-Leigh TL Tamagnini Francesco F Piegsa Judith J Sung Katherine K Harvey Joshua J Oliver-Evans Alice A Murray Tracey K TK Ahmed Zeshan Z Hutton Michael L ML Randall Andrew A O'Neill Michael J MJ Jackson Johanna S JS

Scientific reports 20191016 1

Alzheimer's disease (AD)-associated synaptic dysfunction drives the progression of pathology from its earliest stages. Amyloid β (Aβ) species, both soluble and in plaque deposits, have been causally related to the progressive, structural and functional impairments observed in AD. It is, however, still unclear how Aβ plaques develop over time and how they progressively affect local synapse density and turnover. Here we observed, in a mouse model of AD, that Aβ plaques grow faster in the earlier s ...[more]

PMID: 31619689

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Project description:Local neocortical circuits play critical roles in information processing, including synaptic plasticity, circuit physiology, and learning, and GABAergic inhibitory interneurons have key roles in these circuits. Moreover, specific neurological disorders, including schizophrenia and autism, are associated with deficits in GABAergic transmission in these circuits. GABAergic synapses represent a small fraction of neocortical synapses, and are embedded in complex local circuits that contain many neuron and synapse types. Thus, it is challenging to study the physiological roles of GABAergic inhibitory interneurons and their synapses, and to develop treatments for the specific disorders caused by dysfunction at these GABAergic synapses. To these ends, we report a novel technology that can deliver different genes into pre- and post-synaptic neocortical interneurons connected by a GABAergic synapse: First, standard gene transfer into the presynaptic neurons delivers a synthetic peptide neurotransmitter, containing three domains, a dense core vesicle sorting domain, a GABAA receptor-binding domain, a single-chain variable fragment anti-GABAA ß2 or ß3, and the His tag. Second, upon release, this synthetic peptide neurotransmitter binds to GABAA receptors on the postsynaptic neurons. Third, as the synthetic peptide neurotransmitter contains the His tag, antibody-mediated, targeted gene transfer using anti-His tag antibodies is selective for these neurons. We established this technology by expressing the synthetic peptide neurotransmitter in GABAergic neurons in the middle layers of postrhinal cortex, and the delivering the postsynaptic vector into connected GABAergic neurons in the upper neocortical layers. Targeted gene transfer was 61% specific for the connected neurons, but untargeted gene transfer was only 21% specific for these neurons. This technology may support studies on the roles of GABAergic inhibitory interneurons in circuit physiology and learning, and support gene therapy treatments for specific disorders associated with deficits at GABAergic synapses.

Dataset Information

Imbalance in the response of pre- and post-synaptic components to amyloidopathy.

Publications

Imbalance in the response of pre- and post-synaptic components to amyloidopathy.

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