Ten differentially expressed genes were found to be members of the calcium signaling pathway and are illustrated here according to KEGGs prototype. kinase II alpha (CAMK2A), showed similar changes to those observed in mRNA levels. These findings raise the possibility that calcium signaling and other plasticity molecules may contribute to the hippocampal plasticity and behavioral deficits observed in GluR1 KO mice. Keywords:AMPA, receptor, microarray, neuron, synaptic == Introduction == Ionotropic glutamate receptors mediate most excitatory synaptic transmission in the mammalian central nervous system (CNS). Three major classes of these receptors are expressed throughout the CNS. They are categorized on the basis of pharmacological criteria and primary sequence similarity as -amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA) receptors. These receptors are critically involved in activity-dependent, long-term changes in synaptic strength and, therefore, are central to processes thought to underlie a variety of long-term plasticity events in the hippocampus. AMPA receptors (AMPARs) comprise four subunitsGluR1, GluR2, GluR3, and GluR4 (alternatively called GluRA-D)that combine to form tetramers. The subunit composition of AMPARs varies with cell type, development, and brain region (Seeburget al., 2001). A number of studies indicate that the synaptic delivery of different AMPAR subunit combinations is governed by molecular rules encoded in the intracellular C-terminals of the receptor subunits (Malinow, 2003). Phosphorylation of serines 831 and 845 (S831 and S845) in the GluR1 subunit by calcium-calmodulin-dependent protein kinase II (CaMKII) and cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA), respectively, regulates the ion Folinic acid calcium salt (Leucovorin) channel properties and synaptic trafficking of GluR1-containing AMPARs during hippocampal long-term potentiation (LTP) (Barriaet al., 1997;Derkachet al., 1999;Esteban, 2003). Dephosphorylation of the GluR1 subunit at its PKA site by protein phosphatases (e.g., calcineurin and PP1) targets GluR1 for recycling endosomes during long-term depression (LTD), while re-phosphorylation by PKA may target the receptor for reinsertion into the membrane (Bankeet al., 2000). In addition, mitochondria are also able to modulate synaptic plasticity through cleavage of GluR1 mediated by activation of caspase-3. Exposure of radio-labeled GluR1 to recombinant caspase-3 results in GluR1 cleavage, demonstrating that this glutamate receptor protein is a direct substrate of caspase-3, which can be up-regulated CD59 by cytochrome C release from mitochondria (Luet al., 2002). In GluR1 knockout (KO) mice, initiation or completion of synaptic AMPAR exchange is compromised (McCormacket al., 2006). Gene-targeted mice lacking the AMPAR subunit GluR1 have deficits in hippocampal CA3-CA1 LTP (Zamanilloet al., 1999), suggesting that GluR1 is essential to several forms of hippocampal plasticity. Several studies have evaluated the role of GluR1 in learning, memory, and behavioral plasticity using mutant mice. Furthermore, a variety of behavioral Folinic acid calcium salt (Leucovorin) tests have shown that GluR1-deficient Folinic acid calcium salt (Leucovorin) mice display abnormalities in several behaviors, notably those involving learning/memory (Reiselet al., 2002;Mead & Stephens, 2003;Bannermanet al., 2004; Schmittet al., 2005; Wiedholzet al., 2008). Although these findings point to a critical role for GluR1 in hippocampal behavioral plasticity, the question of the precise downstream gene expression pathways that may underlie these deficits remains. In an effort to identify additional, and perhaps novel, targets underlying these synaptic and behavioral changes in GluR1 KO mice, we conducted the present series of studies to clarify changes associated with GluR1 ablation at the whole genome transcriptional level. == Materials and Methods == == Animal study == The breeding of male C57BL6 GluR1 (GRIA1 or GluR-A) KO mice (GluR1/) has been previously described (Zamanilloet al., 1999). The founding knockout (KO) mice were provided by Dr. Rolf Sprengel (Max Planck Institute for Medical Research, Heidelberg, Germany). Homozygous (GluR1/), heterozygous (GluR1+/), and wild-type (WT) (GluR1+/+) mice were maintained in the animal facility.