Dataset Information

Amyloid Beta Peptides Block New Synapse Assembly by Nogo Receptor-Mediated Inhibition of T-Type Calcium Channels.

ABSTRACT: Compelling evidence links amyloid beta (A?) peptide accumulation in the brains of Alzheimer's disease (AD) patients with the emergence of learning and memory deficits, yet a clear understanding of the events that drive this synaptic pathology are lacking. We present evidence that neurons exposed to A? are unable to form new synapses, resulting in learning deficits in vivo. We demonstrate the Nogo receptor family (NgR1-3) acts as A? receptors mediating an inhibition of synapse assembly, plasticity, and learning. Live imaging studies reveal A? activates NgRs on the dendritic shaft of neurons, triggering an inhibition of calcium signaling. We define T-type calcium channels as a target of A?-NgR signaling, mediating A?'s inhibitory effects on calcium, synapse assembly, plasticity, and learning. These studies highlight deficits in new synapse assembly as a potential initiator of cognitive pathology in AD, and pinpoint calcium dysregulation mediated by NgRs and T-type channels as key components. VIDEO ABSTRACT.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC6101033 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Amyloid Beta Peptides Block New Synapse Assembly by Nogo Receptor-Mediated Inhibition of T-Type Calcium Channels.

Zhao Yanjun Y Sivaji Sivaprakash S Chiang Michael C MC Ali Haadi H Zukowski Monica M Ali Sareen S Kennedy Bryan B Sklyar Alex A Cheng Alice A Guo Zihan Z Reed Alexander K AK Kodali Ravindra R Borowski Jennifer J Frost Georgia G Beukema Patrick P Wills Zachary P ZP

Neuron 20171001 2

Compelling evidence links amyloid beta (Aβ) peptide accumulation in the brains of Alzheimer's disease (AD) patients with the emergence of learning and memory deficits, yet a clear understanding of the events that drive this synaptic pathology are lacking. We present evidence that neurons exposed to Aβ are unable to form new synapses, resulting in learning deficits in vivo. We demonstrate the Nogo receptor family (NgR1-3) acts as Aβ receptors mediating an inhibition of synapse assembly, plasticit ...[more]

PMID: 29024660

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Project description:Background and purposePre-synaptic neurotransmitter release is largely dependent on Ca(2+) entry through P/Q-type (Ca(V)2.1) voltage-gated Ca(2+) channels (PQCCs) at most mammalian, central, fast synapses. Barbiturates are clinical depressants and inhibit pre-synaptic Ca(2+) entry. PQCC barbiturate pharmacology is generally unclear, specifically in man. The pharmacology of the barbiturate pentobarbital (PB) in human recombinant alpha(1A) PQCCs has been characterized.Experimental approachPB effects on macroscopic Ca(2+)(I(Ca)) and Ba(2+)(I(Ba)) currents were studied using whole-cell patch clamp recording in HEK-293 cells heterologously expressing (alpha(1A))(human)(beta(2a)alpha(2)delta-1)(rabbit) PQCCs.Key resultsPB reversibly depressed peak current (I(peak)) and enhanced apparent inactivation (fractional current at 800 ms, r(800)) in a concentration-dependent fashion irrespective of charge carrier (50% inhibitory concentration: I(peak), 656 microM; r(800), 104 microM). Rate of mono-exponential I(Ba) decay was linearly dependent on PB concentration. PB reduced channel availability by deepening non-steady-state inactivation curves without altering voltage dependence, slowed recovery from activity-induced unavailable states and produced use-dependent block. PB (100 microM) induced use-dependent block during physiological, high frequency pulse trains and overall depressed PQCC activity by two-fold.Conclusion and implicationsThe results support a PB pharmacological mechanism involving a modulated receptor with preferential slow, bimolecular, open channel block (K(d)= 15 microM). Clinical PB concentrations (<200 microM) inhibit PQCC during high frequency activation that reduces computed neurotransmitter release by 16-fold and is comparable to the magnitude of Ca(2+)-dependent facilitation, G-protein modulation and intrinsic inactivation that play critical roles in PQCC modulation underlying synaptic plasticity. The results are consistent with the hypothesis that PB inhibition of PQCCs contributes to central nervous system depression underlying anticonvulsant therapy and general anaesthesia.

Dataset Information

Amyloid Beta Peptides Block New Synapse Assembly by Nogo Receptor-Mediated Inhibition of T-Type Calcium Channels.

Publications

Amyloid Beta Peptides Block New Synapse Assembly by Nogo Receptor-Mediated Inhibition of T-Type Calcium Channels.

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