Induction and expression of GluA1 (GluR‐A)‐independent LTP in the hippocampus

Abstract

Long-term potentiation (LTP) at hippocampal CA3-CA1 synapses is thought to be mediated, at least in part, by an increase in the postsynaptic surface expression of a-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptors induced by N-methyld-aspartate (NMDA) receptor activation. While this process was originally attributed to the regulated synaptic insertion of GluA1 (GluR-A) subunit-containing AMPA receptors, recent evidence suggests that regulated synaptic trafficking of GluA2 subunits might also contribute to one or several phases of potentiation. However, it has so far been difficult to separate these two mechanisms experimentally. Here we used genetically modified mice lacking the GluA1 subunit (Gria1 ) ⁄ ) mice) to investigate GluA1-independent mechanisms of LTP at CA3-CA1 synapses in transverse hippocampal slices. An extracellular, paired theta-burst stimulation paradigm induced a robust GluA1-independent form of LTP lacking the early, rapidly decaying component characteristic of LTP in wild-type mice. This GluA1-independent form of LTP was attenuated by inhibitors of neuronal nitric oxide synthase and protein kinase C (PKC), two enzymes known to regulate GluA2 surface expression. Furthermore, the induction of GluA1-independent potentiation required the activation of GluN2B (NR2B) subunit-containing NMDA receptors. Our findings support and extend the evidence that LTP at hippocampal CA3-CA1 synapses comprises a rapidly decaying, GluA1-dependent component and a more sustained, GluA1-independent component, induced and expressed via a separate mechanism involving GluN2B-containing NMDA receptors, neuronal nitric oxide synthase and PKC.

Hippocampal synaptic plasticity, spatial memory and anxiety

“…The GluA1 subunit is thought to play an important role in aspects of AMPAR trafficking 135,136 and in mechanisms underlying synaptic plasticity, particularly short-term forms of plasticity 130,[137][138][139] . GluA1 is also important for SWM performance 20,129,140 .…”

The Effects of GluA1 Deletion on the Hippocampal Population Code for Position

“…Surprising alterations were also observed in the temporal structure of GluA1 Ϫ/Ϫ neurons, spiking such that, despite slightly reduced excitatory transmission attributable to the removal of GluA1 (Andrásfalvy et al, 2003;Jensen et al, 2003;Romberg et al, 2009), the GluA1 Ϫ/Ϫ place cells were more likely to spike in bursts than WT, although they had lower peak intra-burst frequencies.…”

“…To this end, we studied the hippocampal population code for space in the dorsal CA1 region of mice lacking the GluA1 AMPAR subunit. In vitro, hippocampal neurons from these GluA1 Ϫ/Ϫ mice show a lack of tetanically induced long-term potentiation (LTP) (Zamanillo et al, 1999;Romberg et al, 2009), as well as an impaired fast component of theta-burst plasticity (Hoffman et al, 2002;Frey et al, 2009;Romberg et al, 2009). However, more physiologically relevant forms of plasticity, such as the long-term component of theta-burst plasticity, as well as spike-timing-dependent plasticity (STDP), are unaltered in the hippocampus and neocortex (Hoffman et al, 2002;Frey et al, 2009;Romberg et al, 2009).…”

“…In vitro, hippocampal neurons from these GluA1 Ϫ/Ϫ mice show a lack of tetanically induced long-term potentiation (LTP) (Zamanillo et al, 1999;Romberg et al, 2009), as well as an impaired fast component of theta-burst plasticity (Hoffman et al, 2002;Frey et al, 2009;Romberg et al, 2009). However, more physiologically relevant forms of plasticity, such as the long-term component of theta-burst plasticity, as well as spike-timing-dependent plasticity (STDP), are unaltered in the hippocampus and neocortex (Hoffman et al, 2002;Frey et al, 2009;Romberg et al, 2009). Additionally, GluA1 Ϫ/Ϫ hippocampal CA1 pyramidal neurons have strongly reduced extrasynaptic AMPA currents (Andrásfalvy et al, 2003;Romberg et al, 2009) and do not show the dendritic distancedependent scaling of excitatory synaptic strengths seen in WT neurons (Andrásfalvy et al, 2003).…”

“…However, more physiologically relevant forms of plasticity, such as the long-term component of theta-burst plasticity, as well as spike-timing-dependent plasticity (STDP), are unaltered in the hippocampus and neocortex (Hoffman et al, 2002;Frey et al, 2009;Romberg et al, 2009). Additionally, GluA1 Ϫ/Ϫ hippocampal CA1 pyramidal neurons have strongly reduced extrasynaptic AMPA currents (Andrásfalvy et al, 2003;Romberg et al, 2009) and do not show the dendritic distancedependent scaling of excitatory synaptic strengths seen in WT neurons (Andrásfalvy et al, 2003). Behaviorally, the GluA1 Ϫ/Ϫ mice display profound impairments on several different spatial working memory tasks but perform as well as WT animals on spatial reference memory tasks (Zamanillo et al, 1999;Reisel et al, 2002;Schmitt et al, 2003).…”