Abstract
The GluA1 subunit of the L-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) plays a crucial, but highly selective, role in cognitive function. Here we analyzed AMPAR expression, AMPAR distribution and spatial learning in mice (Gria1R/R), expressing the “trafficking compromised” GluA1(Q600R) point mutation. Our analysis revealed somatic accumulation and reduction of GluA1(Q600R) and GluA2, but only slightly reduced CA1 synaptic localization in hippocampi of adult Gria1R/R mice. These immunohistological changes were accompanied by a strong reduction of somatic AMPAR currents in CA1, and a reduction of plasticity (short-term and long-term potentiation, STP and LTP, respectively) in the CA1 subfield following tetanic and theta-burst stimulation. Nevertheless, spatial reference memory acquisition in the Morris water-maze and on an appetitive Y-maze task was unaffected in Gria1R/R mice. In contrast, spatial working/short-term memory during both spontaneous and rewarded alternation tasks was dramatically impaired. These findings identify the GluA1(Q600R) mutation as a loss of function mutation that provides independent evidence for the selective role of GluA1 in the expression of short-term memory.
Highlights
In the central nervous system (CNS) of adult mice L-α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid receptors (AMPARs) are essential for fast synaptic transmission, hippocampal plasticity and behavioral performance
Since in heterologous systems the GluA1(Q600R) point mutation is trafficking compromised (Greger et al, 2003), and since hippocampal GluA2 expression levels are reduced in absence of GluA1 (Jensen et al, 2003), we first analyzed the expression and the channel assembly of AMPARs in Gria1R/R mice by immunoblots and co-IPs
Our analysis of hippocampal protein extracts isolated at different postnatal days (P2 – P90) from controls and Gria1R/R mice showed that the dominant partner GluA2 and GluA1(Q600R) itself were reduced in Gria1R/R animals (Figure 1A)
Summary
In the central nervous system (CNS) of adult mice L-α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid receptors (AMPARs) are essential for fast synaptic transmission, hippocampal plasticity and behavioral performance. GluA4 is not involved in AMPARmediated signal transmission in excitatory neurons of adult mice (Monyer et al, 1991; Zhu et al, 2000; Pelkey et al, 2016; Luchkina et al, 2017). (Q/R) site-editing deficient Gria2∆ECS mice die from epileptic seizures during adolescence (Brusa et al, 1995) but survive when the edited glutamine codon (CAG; Q) was replaced by an arginine codon (CGG; R; GluA2(Q607R)) in gene targeted mice (Kask et al, 1998; Higuchi et al, 2000)
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