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    • The mammalian AMPA receptor protein family comprises four su

    2021-10-19

    The mammalian AMPA receptor protein family comprises four subunits, termed GluR-A through GluR-D (or GluR1 through GluR4), which form hetero-tetrameric receptor complexes Dingledine et al. 1999, Rosenmund et al. 1998. These subunits possess distinctive intracellular C-terminal domains that can be grouped, according to length and sequence, into “short,” 50 amino cgk synthesis residue GluR-B and GluR-C peptides, and “long,” 68 and 81 residue GluR-D and GluR-A peptides, respectively. The critical function of the C-terminal domains is to mediate subunit-specific interactions with proteins for regulating transport, synaptic insertion, synaptic membrane retention, and local synaptic recycling Braithwaite et al. 2000, Sheng and Lee 2001, Barry and Ziff 2002, Song and Huganir 2002. In adult hippocampus, the two major AMPA receptor populations consist of the GluR-A/GluR-B and GluR-B/GluR-C complexes (Wenthold et al., 1996). The synaptic insertion of the GluR-A/GluR-B receptors is activity dependent and is regulated by the GluR-A subunit: postsynaptic Ca2+ influx via NMDA-type glutamate receptors activates the calcium/calmodulin-dependent protein kinase II, CaMKII, leading to ras-mediated activation of the p42/44 mitogen-activated protein kinase Hayashi et al. 2000, Shi et al. 2001, Zhu et al. 2002. This signaling cascade is triggered by strong synaptic activity, such as during brief high-frequency stimulation (tetanus) or low-frequency stimulation paired with prolonged postsynaptic depolarization (pairing protocol), and results in the induction of GluR-A-dependent LTP (Zhu et al., 2002). The GluR-B/GluR-C receptors, on the other hand, are delivered constitutively to the synaptic surface via a GluR-B-mediated interaction with N-ethylmaleimide-sensitive fusion protein (NSF) and class II PDZ domain proteins (Shi et al., 2001). This GluR-B-mediated activity-independent transport is believed to replace synaptic AMPA receptors without changing the synaptic efficacy (Zhu et al., 2000). A critical importance of the GluR-A subunit for glutamatergic plasticity and learning was demonstrated in mice lacking a functional GluR-A gene: in hippocampal slices prepared from adult GluR-A−/− animals tetanic, stimulation failed to elicit LTP at CA3-CA1 synapses (Zamanillo et al., 1999), and the mice had severely impaired spatial working memory (Reisel et al., 2002). However, the GluR-A−/− mice showed normal development of hippocampal excitatory circuitry and normal spatial reference memory in a water maze learning in the adult, both processes presumably also requiring hippocampal synaptic plasticity (Zamanillo et al., 1999). Indeed, GluR-A-independent forms of hippocampal CA3 to CA1 LTP in juvenile as well as in adult animals were recently reported Hoffman et al. 2002, Jensen et al. 2003. While the mechanisms for these forms of glutamatergic synaptic plasticity in the GluR-A−/− animals are not known, a possible scenario may include AMPA receptor delivery regulated by a subunit different from GluR-A. Notably, the GluR-B primary transcript gives rise to two C-terminal alternative splice variants, a “short” form referred to as GluR-B (above), and a “long” form termed GluR-Blong (Kohler et al., 1994). GluR-Blong contains a 68 amino residue C-terminal domain that shows 63% identity with the GluR-D C-terminal domain. Until now, the expression profile of GluR-Blong and the role of GluR-Blong in AMPA receptor-mediated synaptic transmission have not been investigated. Here we describe the developmental and regional expression of GluR-Blong, its steady-state oligomerization with other AMPA receptor subunits, and its mode of synaptic delivery. We show that GluR-Blong synaptic insertion is activity dependent, triggered by spontaneous synaptic activity and following the induction of LTP. The overall significance of GluR-Blong-mediated AMPA receptor trafficking, as examined by expression of the EGFP-tagged GluR-Blong C-terminal domain predicted to interfere with the transport of endogenous GluR-Blong receptors, was 2-fold. First, inhibition of GluR-Blong delivery by spontaneous synaptic activity resulted in ∼35% reduction of the steady-state AMPA receptor responses in young postnatal day 14 (P14) CA1 pyramidal neurons. Second, inhibition of GluR-Blong transport during the induction of LTP resulted in ∼50% reduction of the established potentiation in P14 CA1 neurons of rat organotypic slices, and in a complete loss of LTP in P14 CA1 neurons of slices prepared from mice lacking the GluR-A subunit. Taken together, these data show that GluR-Blong-containing AMPA receptors provide a GluR-A-independent transport mechanism for the induction of glutamatergic synaptic plasticity, a function which is significantly utilized in young CA1 neurons.