Abstract
Excitatory synaptic transmission is mediated by AMPA-type glutamate receptors (AMPARs). In CA1 pyramidal neurons of the hippocampus two types of AMPARs predominate: those that contain subunits GluA1 and GluA2 (GluA1/2), and those that contain GluA2 and GluA3 (GluA2/3). Whereas subunits GluA1 and GluA2 have been extensively studied, the contribution of GluA3 to synapse physiology has remained unclear. Here we show in mice that GluA2/3s are in a low-conductance state under basal conditions, and although present at synapses they contribute little to synaptic currents. When intracellular cyclic AMP (cAMP) levels rise, GluA2/3 channels shift to a high-conductance state, leading to synaptic potentiation. This cAMP-driven synaptic potentiation requires the activation of both protein kinase A (PKA) and the GTPase Ras, and is induced upon the activation of β-adrenergic receptors. Together, these experiments reveal a novel type of plasticity at CA1 hippocampal synapses that is expressed by the activation of GluA3-containing AMPARs.
Highlights
AMPA-type glutamate receptors (AMPARs) are responsible for fast excitatory synaptic transmission in the brain
To examine the contribution of GluA3 to the pool of extra-synaptic AMPARs, we recorded currents evoked by puffing AMPA onto outside-out membrane patches excised from cell bodies of CA1 pyramidal neurons in organotypic hippocampal slices prepared from wild-type, GluA3-deficient or GluA1-deficient mice (Figure 1A,B)
In this study we identified a novel form of synaptic plasticity in the CA1 region of the hippocampus that depends on GluA3-containing AMPARs
Summary
AMPA-type glutamate receptors (AMPARs) are responsible for fast excitatory synaptic transmission in the brain. Upon the induction of long-term potentiation (LTP) or upon learning GluA1-containing AMPARs traffic into synapses, whereas a selective blockade of GluA1-trafficking prevent the expression of LTP and impairs memory formation (Kessels and Malinow, 2009; Mitsushima et al, 2011; Rumpel et al, 2005). The C-tail of GluA1 can be phosphorylated by protein kinase A (PKA) upon a rise in the levels of intracellular cyclic AMP (cAMP), which promotes GluA1-trafficking, lowers the threshold for LTP and facilitates the formation of memories (Crombag et al, 2008; Esteban et al, 2003; Hu et al, 2007; Qian et al, 2012). A recent study extended the AMPAR subunit-specific plasticity rules by showing that the N-terminal domain (NTD) of AMPAR subunits controls the anchoring of AMPARs at synapses, with a more stable anchoring of by the GluA2 NTD compared with the GluA1 NTD (Watson et al, 2017)
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