The 22q11 deletion syndrome (22q11DS) is characterized by cognitive decline and increased risk of psychiatric disorders, mainly schizophrenia. The molecular mechanisms of neuronal dysfunction in cognitive symptoms of 22q11DS are poorly understood. Here, we report that a mouse model of 22q11DS, the Df(16)1/؉ mouse, exhibits substantially enhanced short-and long-term synaptic plasticity at hippocampal CA3-CA1 synapses, which coincides with deficits in hippocampus-dependent spatial memory. These changes are evident in mature but not young animals. Electrophysiological, two-photon imaging and glutamate uncaging, and electron microscopic assays in acute brain slices showed that enhanced neurotransmitter release but not altered postsynaptic function or structure caused these changes. Enhanced neurotransmitter release in Df(16)1/؉ mice coincided with altered calcium kinetics in CA3 presynaptic terminals and upregulated sarco(endo)plasmic reticulum calcium-ATPase type 2 (SERCA2). SERCA inhibitors rescued synaptic phenotypes of Df(16)1/؉ mice. Thus, presynaptic SERCA2 upregulation may be a pathogenic event contributing to the cognitive symptoms of 22q11DS.

Regulator of G protein signaling (RGS) proteins negatively regulate receptor-mediated second messenger responses by enhancing the GTPase activity of G␣ subunits. We describe a receptor-specific role for an RGS protein at the level of an individual brain neuron. RGS9-2 and G␤5 mRNA and protein complexes were detected in striatal cholinergic and ␥-aminobutyric acidergic neurons. Dialysis of cholinergic neurons with RGS9 constructs enhanced basal Ca 2؉ channel currents and reduced D2 dopamine receptor modulation of Cav2.2 channels. These constructs did not alter M2 muscarinic receptor modulation of Cav2.2 currents in the same neuron. The noncatalytic DEP-GGL domain of RGS9 antagonized endogenous RGS9-2 activity, enhancing D2 receptor modulation of Ca 2؉ currents. In vitro, RGS9 constructs accelerated GTPase activity, in agreement with electrophysiological measurements, and did so more effectively at Go than Gi. These results implicate RGS9-2 as a specific regulator of dopamine receptor-mediated signaling in the striatum and identify a role for GAP activity modulation by the DEP-GGL domain.calcium ͉ GTPase activating protein ͉ receptor-specific ͉ basal ganglia ͉ indirect pathway R egulators of G protein signaling (RGS) are a diverse family of proteins identified by the presence of a 120-aa domain termed the RGS box. In cell lines or in purified in vitro assays, most RGS proteins enhance the GTPase activity of heterotrimeric G protein ␣ subunits and thereby accelerate the deactivation of receptor-initiated second messenger responses. Many RGS proteins also contain one or more putative protein-protein interaction domains. These noncatalytic domains have been suggested to regulate catalytic activity, signal transduction pathway specificity, and͞or subcellular targeting of RGS proteins.One subfamily of RGS proteins (RGS6, -7, -9, and -11) all share homologous DEP (Dishevelled, Egl-10, Pleckstrin), GGL (G protein Gamma subunit Like), and RGS domains. The DEP domain of the retinal isoform of RGS9 (RGS9-1) has been shown to confer localization to a retinal membrane protein termed R9AP, and this localization has been shown to be necessary for proper RGS9-1 function in the retina (1). Several investigators have demonstrated that the GGL domain interacts with the G␤ 5 subunit (2-6). In vitro, G␤ 5 binding to RGS6, -7, or -11 increases the GAP specificity of these RGS proteins for G␣ (2, 3). In addition, G␤ 5 binding to either RGS7 or RGS9 enhances RGS-mediated acceleration of G protein gated inwardly rectifying K ϩ (Kir3) channel activation and deactivation kinetics in an oocyte expression system. This enhancement may result from G␤ 5 -mediated increased stability of the RGS protein or enhanced GAP activity (7).Despite the functional similarities among RGS6, -7, -9, and -11 in heterologous expression systems or when analyzed in vitro, each of these RGS proteins is likely to play a unique role in the central nervous system because they are differentially localized within the brain (8, 9). In contrast to the more ubiquitous loc...

Hemizygous deletion of a 1.5- to 3-megabase region on chromosome 22 causes 22q11.2 deletion syndrome (22q11DS), which constitutes one of the strongest genetic risks for schizophrenia. Mouse models of 22q11DS have abnormal short-term synaptic plasticity (STP) that contributes to working memory deficiencies similar to those in schizophrenia. We screened mutant mice carrying hemizygous deletions of 22q11DS genes and identified haploinsufficiency of Mrpl40 (mitochondrial large ribosomal subunit protein 40) as a contributor to abnormal STP. Two-photon imaging of the genetically encoded fluorescent calcium indicator GCaMP6, expressed in presynaptic cytosol or mitochondria, showed that Mrpl40 haploinsufficiency deregulates STP via impaired calcium extrusion from the mitochondrial matrix through the mitochondrial permeability transition pore. This led to abnormally high cytosolic calcium transients in presynaptic terminals and deficient working memory but did not affect long-term spatial memory. Thus, we propose that mitochondrial calcium deregulation is a novel pathogenic mechanism of cognitive deficiencies in schizophrenia.