GluA4 Dependent Plasticity Mechanisms Contribute to Developmental Synchronization of the CA3–CA1 Circuitry in the Hippocampus

Abstract

During the course of development, molecular mechanisms underlying activity-dependent synaptic plasticity change considerably. At immature CA3-CA1 synapses in the hippocampus, PKA-driven synaptic insertion of GluA4 AMPA receptors is the predominant mechanism for synaptic strengthening. However, the physiological significance of the developmentally restricted GluA4-dependent plasticity mechanisms is poorly understood. Here we have used microelectrode array (MEA) recordings in GluA4 deficient slice cultures to study the role of GluA4 in early development of the hippocampal circuit function. We find that during the first week in culture (DIV2-6) when GluA4 expression is restricted to pyramidal neurons, loss of GluA4 has no effect on the overall excitability of the immature network, but significantly impairs synchronization of the CA3 and CA1 neuronal populations. In the absence of GluA4, the temporal correlation of the population spiking activity between CA3-CA1 neurons was significantly lower as compared to wild-types at DIV6. Our data show that synapse-level defects in transmission and plasticity mechanisms are efficiently compensated for to normalize population firing rate at the immature hippocampal network. However, lack of the plasticity mechanisms typical for the immature synapses may perturb functional coupling between neuronal sub-populations, a defect frequently implicated in the context of developmentally originating neuropsychiatric disorders.

Effect of Aggressive Experience in Female Syrian Hamsters on Glutamate Receptor Expression in the Nucleus Accumbens

“…Furthermore, although GluA4 has been primarily only implicated in neurodevelopment, we also observed a non-significant trend for increased expression in GluA4 1 week following aggressive experience, suggesting that it may play a role in the longlasting behavioral effects of aggression (Huupponen et al, 2016;Luchkina et al, 2017;Atanasova et al, 2019).…”

Subunit‐specific expression and function of AMPA receptors in the mouse locus coeruleus

“…In the cortex, the synaptic incorporation of GluA4 subunit‐containing AMPA receptors has been shown to be instrumental in the functional development of glutamatergic synapses (Luchkina et al, 2017 ). Furthermore, these receptors contribute to synaptic plasticity underlying synchronisation of hippocampal circuitry instrumental during development (Atanasova et al, 2019 ). This could be of particular relevance to the GluA4 subunit during the early development of the LC when establishing its connectivity patterns with other brain regions.…”