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Open Access Publications from the University of California

Cellular and molecular studies on hippocampal plasticity: region-dependent effects of β-adrenergic signaling and the regulation of AMPA receptor phosphorylation

  • Author(s): Guglietta, Ryan T.
  • Advisor(s): O'Dell, Thomas
  • et al.
Abstract

Synaptic plasticity is an essential mechanism for both the creation of memories and the

formation of associations between those memories. A crucial component of learning and

memory is the hippocampus. The works included in this thesis probe the cellular basis of

learning and memory in the hippocampus through two primary means. The first builds upon

existing information highlighting the stark difference in plasticity between the dorsal and ventral poles of the hippocampus along with the preferential influence of neuromodulators

on ventral plasticity. The second examines the importance of phosphorylation-based regulation of the AMPA receptor subunit, GluA1, and how this mediates hippocampal plasticity.

Despite similar basal excitatory and inhibitory synaptic transmission between the two

poles, the ventral hippocampus exhibits much weaker long term potentiation (LTP) and complex spiking compared to the dorsal. This deficit was due to a down regulation of the NMDA receptors in the ventral region, which resulted in weaker E-S coupling and EPSP amplification. LTP induction and complex spiking, however, could be rescued with the addition of a β-adrenergic agonist. Additionally, β-adrenergic activation inhibited the small conductance calcium-activated potassium channel, SK, which serves to hyperpolarize the cell and resist NMDA receptor activation. Indeed, pharmacological inhibition of the SK channel enhanced LTP induction, complex spiking, E-S coupling, and EPSP amplification in the ventral hippocampus.

The second part of this thesis examined the role of two particular GluA1 phosphorylation

sites, S845 and T840, and how their phosphorylation states affect hippocampal plasticity. We

found that S845 and T840 are regulated by distinct calcium sources and phosphatases and also track synaptic strength in different ways. S845 is persistently dephosphorylated following either depolarization or LTD induction, whereas T840 only remains dephosphorylated after LTD induction. Furthermore, we found inhibitory phospho-site interactions between the two sites, due to their close proximity to one another. We then determined the basal phosphorylation levels of both sites and discovered that S845 phosphorylation levels were so low we could not adequately quantify them while T840 residues were phosphorylated in approximately ~50% of GluA1 subunits.

This thesis has served two important roles in the elucidation of plasticity in the

hippocampus, as it has i) identified a potent role of noradrenergic signaling in facilitating LTP

induction in the ventral hippocampus and ii) detailed the regulation and prevalence of T840 and S845 in the hippocampus, along with their involvement in plasticity.

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