Glutamate receptor composition in ageing human brain and in mouse models of synaptic degeneration

Abstract

Neurodegenerative diseases, which involve progressive loss of structure and function of neurons, and ageing are often associated with cognitive decline. With an increase in the ageing population, we need better understanding of the neuronal changes that underpin this decline.

NMDA receptors (NMDARs) are essential for many forms of synaptic plasticity, a molecular correlate of learning and memory. They consist of 4 subunits; the obligatory GluN1, and regulatory GluN2/3 subunits, which in turn exist in different subtypes. Evidence from rodents has shown a correlation between the content of a GluN2 receptor subtype, GluN2B, at the synapses of neurons and performance in memory tasks. Further evidence in transgenic mice, suggests that recruitment of GluN2B containing receptors at the synapse, has a vital role in regulating synaptic strength and memory storage.

My aim was to investigate whether age-dependent changes in synaptic GluN2B composition occur in the ageing human brain, and in mouse models harbouring mutations associated with neurodegenerative diseases. To address this question, we decided to analyse the synaptic composition of excitatory pyramidal neurons using electrophysiological and biochemical methods.

We obtained electrophysiological patch-clamp recordings in neurons from:
1.Adult living temporal cortical tissue resected during neurosurgery and
2.Mouse models expressing proteins that harbour mutations associated with familial forms of neurodegenerative diseases.

By analysing inputs to pyramidal neurons using whole-cell voltage clamp, we measured NMDA receptor- and AMPA receptor-mediated currents prior to, and following pharmacological block of GluN2B subunit. Via the use of co-immunoprecipitation, we analysed the association of GluN2 subunits with synaptic proteins.

Our findings indicate that a significant fraction of GluN2B-containing NMDARs exists in LII-III pyramidal neuron synapses in young adults, and that this synaptic component declines with age. Our findings using mouse models, suggested a minimal contribution of GluN2B subunits at the synapses.

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Identifiers

ORCID for Mariana Vargas-Caballero: orcid.org/0000-0003-2326-4001

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