Memory is essential for our normal daily lives and our sense of self. Ca2+ influx through the NMDA‐type glutamate receptor (NMDAR) and the ensuing activation of the Ca2+ and calmodulin‐dependent protein kinase (CaMKII) are required for memory formation and its physiological correlate, long‐term potentiation (LTP). The Ca2+ influx induces CaMKII binding to the NMDAR to strategically recruit CaMKII to synapses that are undergoing potentiation. We generated mice with two point mutations that impair CaMKII binding to the NMDAR GluN2B subunit. Ca2+‐triggered postsynaptic accumulation is largely abrogated for CaMKII and destabilized for TARPs, which anchor AMPA‐type glutamate receptors (AMPAR). LTP is reduced by 50% and phosphorylation of the AMPAR GluA1 subunit by CaMKII, which enhances AMPAR conductance, impaired. The mutant mice learn the Morris water maze (MWM) as well as WT but show deficiency in recall during the period of early memory consolidation. Accordingly, the activity‐driven interaction of CaMKII with the NMDAR is important for recall of MWM memory as early as 24 h, but not 1–2 h, after training potentially due to impaired consolidation.
Association of PKA with the AMPA receptor GluR1 subunit via the A kinase anchor protein AKAP150 is crucial for GluR1 phosphorylation. Mutating the AKAP150 gene to specifically prevent PKA binding reduced PKA within postsynaptic densities (>70%). It abolished hippocampal LTP in 7–12 but not 4‐week‐old mice. Inhibitors of PKA and of GluR2‐lacking AMPA receptors blocked single tetanus LTP in hippocampal slices of 8 but not 4‐week‐old WT mice. Inhibitors of GluR2‐lacking AMPA receptors also prevented LTP in 2 but not 3‐week‐old mice. Other studies demonstrate that GluR1 homomeric AMPA receptors are the main GluR2‐lacking AMPA receptors in adult hippocampus and require PKA for their functional postsynaptic expression during potentiation. AKAP150‐anchored PKA might thus critically contribute to LTP in adult hippocampus in part by phosphorylating GluR1 to foster postsynaptic accumulation of homomeric GluR1 AMPA receptors during initial LTP in 8‐week‐old mice.
The NR2B subunit of the NMDA receptor interacts with several prominent proteins in the postsynaptic density, including calcium/ calmodulin-dependent protein kinase II (CaMKII). To determine the function of these interactions, we derived transgenic mice expressing a ligand-activated carboxy-terminal NR2B fragment (cNR2B) by fusing this fragment to a tamoxifen (TAM)-dependent mutant of the estrogen receptor ligand-binding domain LBD G521R . Here, we show that induction by TAM allows the transgenic cNR2B fragment to bind to endogenous CaMKII in neurons. Activation of the LBD G521R -cNR2B transgenic protein in mice leads to the disruption of CaMKII/NR2B interactions at synapses. The disruption decreases Thr286 phosphorylation of ␣CaMKII, lowers phosphorylation of a key CaMKII substrate in the postsynaptic membrane (AMPA receptor subunit glutamate receptor 1), and produces deficits in hippocampal long-term potentiation and spatial learning. Together our results demonstrate the importance of interactions between CaMKII and NR2B for CaMKII activity, synaptic plasticity, and learning.
1. The authors' goal was to compare the size and density of Purkinje cells in the cerebellum of subjects with and without autism. Blocks of cerebellum were dissected at autopsy from the brains of age, sex- and postmortem-intervaled (PMI) groups of autistic and normal control individuals (N = 5 per group). Frozen, unfixed blocks were sectioned and stained with 1% cresyl violet. 2. The linear, molecular, granular densities and cross-sectional area of Purkinje cells were measured using computer-assisted image analysis. The average cross-sectional areas of Purkinje cells of the patients with autism were smaller by 24% when compared to the normal subjects. Two of the five autistic subjects had mean Purkinje cell sizes that corresponded to greater than 50% reduction in size. There was a substantial effect size difference in Purkinje cell size (eta2 = 0.29) between control and autistic brains (F(1, 8) = 3.32, P = 0.106). No differences in Purkinje cell densities were observed between the two groups 3. These data indicate the possibility of Purkinje cell atrophy in autism with significant neurohistological heterogeneity among individuals diagnosed with this disorder.
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