Developmental switch in the kinase dependency of long-term potentiation depends on expression of GluA4 subunit-containing AMPA receptors

Abstract

The AMPA-receptor subunit GluA4 is expressed transiently in CA1 pyramidal neurons at the time synaptic connectivity is forming, but its physiological significance is unknown. Here we show that GluA4 expression is sufficient to alter the signaling requirements of long-term potentiation (LTP) and can fully explain the switch in the LTP kinase dependency from PKA to Ca2 + /calmodulin-dependent protein kinase II during synapse maturation. At immature synapses, activation of PKA leads to a robust potentiation of AMPAreceptor function via the mobilization of GluA4. Analysis of GluA4-deficient mice indicates that this mechanism is critical for neonatal PKA-dependent LTP. Furthermore, lentiviral expression of GluA4 in CA1 neurons conferred a PKA-dependent synaptic potentiation and LTP regardless of the developmental stage. Thus, GluA4 defines the signaling requirements for LTP and silent synapse activation during a critical period of synapse development.glutamate receptor | hippocampus | synaptic transmission

Synaptic AMPA receptor composition in development, plasticity and disease

“…Furthermore, PKC phosphorylation of GluA2 is required for cerebellar LTD 135 . Beyond GluA1 and GluA2, transient expression of GluA4 in CA1 pyramidal neurons during early development underpins the switch in kinase signaling in LTP from PKA to CaMKII-dependent mechanisms 136 . PKA activation drives synaptic expression of GluA4, and PKA-mediated recruitment of GluA4-containing AMPARs in immature synapses unsilences silent synapses 136 .…”

“…Beyond GluA1 and GluA2, transient expression of GluA4 in CA1 pyramidal neurons during early development underpins the switch in kinase signaling in LTP from PKA to CaMKII-dependent mechanisms 136 . PKA activation drives synaptic expression of GluA4, and PKA-mediated recruitment of GluA4-containing AMPARs in immature synapses unsilences silent synapses 136 . Surprisingly, recent analysis of the stoichiometry of GluA1 phosphorylation using Phostag SDS-PAGE indicates only ~1% of total GluA1 is phosphorylated at S831 and less than 0.1% is phosphorylated S845.…”

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

“…Moreover, GluA4 -/mice are grossly normal with no apparent morphological changes in the brain (Fuchs et al, 2007;Sagata et al, 2010), suggesting that many of the GluA4 functions at the immature circuitry are efficiently compensated for. Indeed, the GluA4 -/mice show apparently normal LTP at immature CA3-CA1 synapses that is mediated via GluA1 and CaMKII dependent mechanisms, in contrast to the PKA dependent LTP that is predominant at this developmental stage in the WTs (Luchkina et al, 2014). In addition, even if immature synapses in GluA4 deficient mice are less responsive to alterations in network activity, they are capable of synaptic scaling with a higher threshold for induction as compared to WTs (Huupponen et al, 2016).…”

“…PKA-driven synaptic insertion of GluA4 is the predominant mechanism for synaptic strengthening at immature hippocampal synapses (Luchkina et al, 2014;2017;Huupponen et al, 2016). GluA4 is efficiently transported to synapses with initially low or silent AMPA-mediated transmission in response to Hebbian activity (Zhu et al, 2000;Esteban et al, 2003;Luchkina et al, 2017), which is provided by the spontaneously occurring bursts of synchronous activity in the neonatal hippocampus (Kasyanov et al, 2004;Mohajerani et al, 2007;Huupponen et al, 2013Huupponen et al, , 2016.…”

“…Postsynaptically, GluA4 subunits of AMPA receptors are predominantly expressed during the first postnatal week, while the levels of the other subunits are low (Zhu et al, 2000). GluA4 expression is sufficient to alter the signaling mechanisms of LTP and support PKA -dependent LTP at CA3-CA1 synapses (Zhu et al, 2000;Esteban et al, 2003;Yasuda et al, 2003;Luchkina et al, 2014). Indeed, the loss of GluA4 expression at the CA1 pyramidal neurons during postnatal maturation of the circuitry can fully explain the developmental switch in LTP mechanisms from PKA dependent to CaMKII dependent (Yasuda et al, 2003, Luchkina et al 2014.…”