Aberrant Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII) Activity Is Associated with Abnormal Dendritic Spine Morphology in theATRXMutant Mouse Brain

Abstract

In humans, mutations in the gene encoding ATRX, a chromatin remodeling protein of the sucrose-nonfermenting 2 family, cause several mental retardation disorders, including ␣-thalassemia X-linked mental retardation syndrome. We generated ATRX mutant mice lacking exon 2 (ATRX ⌬E2 mice), a mutation that mimics exon 2 mutations seen in human patients and associated with milder forms of retardation. ATRX ⌬E2 mice exhibited abnormal dendritic spine formation in the medial prefrontal cortex (mPFC). Consistent with other mouse models of mental retardation, ATRX ⌬E2 mice exhibited longer and thinner dendritic spines compared with wild-type mice without changes in spine number. Interestingly, aberrant increased calcium/calmodulin-dependent protein kinase II (CaMKII) activity was observed in the mPFC of ATRX ⌬E2 mice. Increased CaMKII autophosphorylation and activity were associated with increased phosphorylation of the Rac1-guanine nucleotide exchange factors (GEFs) T-cell lymphoma invasion and metastasis 1 (Tiam1) and kalirin-7, known substrates of CaMKII. We confirmed increased phosphorylation of p21-activated kinases (PAKs) in mPFC extracts. Furthermore, reduced protein expression and activity of protein phosphatase 1 (PP1) was evident in the mPFC of ATRX ⌬E2 mice. In cultured cortical neurons, PP1 inhibition by okadaic acid increased CaMKII-dependent Tiam1 and kalirin-7 phosphorylation. Together, our data strongly suggest that aberrant CaMKII activation likely mediates abnormal spine formation in the mPFC. Such morphological changes plus elevated Rac1-GEF/PAK signaling seen in ATRX ⌬E2 mice may contribute to mental retardation syndromes seen in human patients.

Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes

“…Of note, transgenic mice with ATRX mutations causing mental retardation in humans showed abnormal dendritic spine formation with increased TIAM1 phosphorylation and Rac1 signalling 27 . We conclude that alterations with significant frequencies (PTPRD and ODZ genes) affect transmembrane receptors that function in neuronal growth cone guidance and maintenance.…”

Expression of a Truncated Form of the Endoplasmic Reticulum Chaperone Protein, σ1 Receptor, Promotes Mitochondrial Energy Depletion and Apoptosis

“…Immunohistochemistry-Fluorescence immunohistochemical studies were performed as described (24). Cells were fixed in 4% paraformaldehyde in phosphate buffer for 30 min at room temperature and washed in PBS.…”

“…Quantification of mRNA by Real Time PCR-Real time PCR analysis was performed as described (24) in 48-well plates (Mini Opticon Real Time PCR System, Bio-Rad) using iQ SYBR Green Supermix 2ϫ (Bio-Rad). Primer sequences are shown in supplemental Table 1.…”

Activity-Dependent Modulation of the Interaction between CaMKIIα and Abi1 and Its Involvement in Spine Maturation

“…Ube3a maternal-deficient mice, a mouse model strain for Angelman syndrome, a disorder characterized by mental retardation and seizures, show increased levels of P-CaMKII␣ in the hippocampus (Weeber et al, 2003). Increased P-CaMKII and activity was also observed in a mouse model for ␣-thalassemia X-linked mental retardation (ATX-R) (Shioda et al, 2011). Our understanding of these neurological diseases, each of which are associated with abnormal dendritic spine formation, may benefit from these studies showing the importance of CaMKII␣ activity in spine regulation.…”