Dysregulation of Presynaptic Calcium and Synaptic Plasticity in a Mouse Model of 22q11 Deletion Syndrome

Abstract

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.

Working Memory Impairment in Calcineurin Knock-out Mice Is Associated with Alterations in Synaptic Vesicle Cycling and Disruption of High-Frequency Synaptic and Network Activity in Prefrontal Cortex

“…Consistent with this concept, mounting evidence from gene profiling, genetic association, and proteomic analyses indicates that alterations in presynaptic function contribute to the etiology of schizophrenia (Chen et al, 2004;Lee et al, 2005;Behan et al, 2009;Maycox et al, 2009;Faludi and Mirnics, 2011). In addition, several studies have reported alterations in presynaptic function or short-term synaptic plasticity in other mouse models of schizophrenia (Jentsch et al, 2009;Talbot, 2009;Blundell et al, 2010;Earls et al, 2010;Kvajo et al, 2011). Critically, our study extends on these findings by revealing an integrated disease mechanism that links presynaptic dysfunction with corresponding effects on higher-order circuit, network, and cognitive functions.…”

“…Moreover, we show that calcineurin deficiency results in a gene dose-dependent impairment of performance in a DNMTP operant working memory task. Last, we provide evidence that a similar alteration in synaptic vesicle cycling may occur in the PFC of schizophrenia patients as a consequence of reduced expression of the presynaptic protein and calcineurin substrate, dynamin I, which has been shown to be specifically required for sustaining high-frequency neuronal firing (Ferguson et al, 2007). Based on these data, we propose a presynaptic mechanistic framework for working memory dysfunction in the context of schizophrenia (Fig.…”

“…Calcineurin dephosphorylates a set of proteins known to be critical for synaptic vesicle cycling (Cousin and Robinson, 2001), likely underlying its positive modulation of this process (Cousin and Robinson, 2001;Sun et al, 2010). A number of reports have indicated a requirement for these presynaptic calcineurin substrates in regulating sustained, high-frequency neuronal activity (Cremona et al, 1999;Di Paolo et al, 2002Ferguson et al, 2007;Clayton et al, 2009;Sun et al, 2010), suggesting a role for calcineurin in the range of neuronal activity associated with working memory. To investigate whether cortical presynaptic function is altered in CN-KO mice, we first examined the phosphorylation status of presynaptic calcineurin substrates in the cerebral cortex of these mice using phospho-specific antibodies.…”

Cognitive, Behavioural and Psychiatric Phenotype in 22q11.2 Deletion Syndrome

“…These deficits were also observed in primary cultures from Zdhhc8-deficient mice and could be prevented by introduction of enzymatically active ZDHHC8 palmitoyltransferase. However, these structural changes were not replicated in Df1(16)1/+ mice (Earls et al 2010). Using this model, Earls et al (Earls et al 2010) reported deficits in spatial memory associated with increased long term potentiation and enhanced pre-synaptic glutamate release in hippocampal CA3-CA1 pyramidal neurons.…”

Hydroxyurea therapy of a murine model of sickle cell anemia inhibits the progression of pneumococcal disease by down-modulating E-selectin

“…22,23 Surgery was performed over the auditory cortex, and cranial windows were installed as described under "Intravital fluorescence microscopy." Rhodamine-dextran (10 000 MW, 1 mg/mouse; Invitrogen) was injected to visualize the vasculature along with the GFP neutrophils.…”