Abstract
We studied the role of Homer1 gene products on the presence of synaptic Ca2+-permeable AMPA receptors (AMPARs) and long-term potentiation (LTP) generation in hippocampal CA1 pyramidal neurons, using mice either lacking all Homer1 isoforms (Homer1 KO) or overexpressing the immediate early gene (IEG) product Homer1a (H1aTG). We found that Homer1 KO caused a significant redistribution of the AMPAR subunit GluA2 from the dendritic compartment to the soma. Furthermore, deletion of Homer1 enhanced the AMPAR-mediated component of glutamatergic currents at Schaffer collateral synapses as demonstrated by increased AMPA/NMDA current ratios. Meanwhile, LTP generation appeared to be unaffected. Conversely, sustained overexpression of Homer1a strongly reduced AMPA/NMDA current ratios and polyamine sensitivity of synaptic AMPAR, indicating that the proportion of synaptic GluA2-containing AMPAR increased relative to WT. LTP maintenance was abolished in H1aTG. Notably, overexpression of Homer1a in Homer1 KO or GluA2 KO mice did not affect LTP expression, suggesting activity-dependent interaction between Homer1a and long Homer1 isoforms with GluA2-containing AMPAR. Thus, Homer1a is essential for the activity-dependent regulation of excitatory synaptic transmission.
Highlights
Synaptic plasticity and memory consolidation are dynamically regulated by the activation of immediate early gene (IEG) expression, which can directly modulate postsynaptic signaling mechanisms in excitatory neurons (Lanahan and Worley, 1998)
We studied the role of Homer1 gene products on the presence of synaptic Ca2+-permeable AMPA receptors (AMPARs) and long-term potentiation (LTP) generation in hippocampal CA1 pyramidal neurons, using mice either lacking all Homer1 isoforms (Homer1 KO) or overexpressing the immediate early gene (IEG) product Homer1a (H1aTG)
We observed a significant redistribution of the AMPAR subunit GluA2 from the dendritic compartment into the cell bodies in CA1 pyramidal neurons of Homer1 KO but not WT mice (Figures 1A–D)
Summary
Synaptic plasticity and memory consolidation are dynamically regulated by the activation of immediate early gene (IEG) expression, which can directly modulate postsynaptic signaling mechanisms in excitatory neurons (Lanahan and Worley, 1998). The IEG-form Homer1a lacks the C-terminal multimerization sequences and competes with long Homer isoforms in binding postsynaptic signaling proteins (Xiao et al, 2000; Duncan et al, 2005; Celikel et al, 2007). In postsynaptic spines of excitatory neurons different Homer isoforms can modulate the function of a variety of synaptic components, including ionotropic and metabotropic glutamate receptors, transient receptor potential channels, shank scaffolding proteins, and endoplasmatic reticulum Ca2+ release channels (Kammermeier et al, 2000; De Bartolomeis and Iasevoli, 2003; Duncan et al, 2005). Other groups could not obtain evidence for the involvement of Ca2+-permeable AMPARs in the initial phase of LTP (Adesnik and Nicoll, 2007; Gray et al, 2007)
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