Regulation of synaptic function and plasticity by cyclin-dependent kinase 5

Thesis (Ph. D. in Neuroscience)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, February 2013.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Cataloged from student-submitted PDF version of thesis. "February 2013." Page 192 blank.Includes bibliographical references.The neuronal serine/threonine kinase cyclin-dependent kinase 5 (Cdk5) is activated by its regulatory subunit, p35, to post-translationally modify substrates through phosphorylation. In this thesis, I provide several lines of evidence that Cdk5 plays a critical role in synaptic function and plasticity. First, we characterized the function of Cdk5 in learning and memory by region-specific Cdk5 ablation. From multiple Cdk5 conditional knockout mouse models, we determined that Cdk5 is essential for memory formation and synaptic plasticity. Loss of Cdk5 in the hippocampus disrupts the cAMP pathway due to increased phosphodiesterase proteins. This dysregulation of cAMP signaling can be attenuated by a phosphodiesterase inhibitor to restore levels of protein phosphorylation, synaptic plasticity, and memory. Moreover, forebrain-specific deletion of Cdk5 affected multiple aspects of behavior that can partially be rescued by lithium treatment. We next identified the N-type calcium channels as a presynaptic substrate of Cdk5. We described how Cdk5-mediated phosphorylation of the N-type calcium channel increased calcium influx and channel open probability. This in turn enhanced the association of the N-type calcium channel with the active zone protein RIM1, which impacted vesicle docking and neurotransmission. Finally, we identified the postsynaptic density protein Shank3 as a Cdk5 substrate and observed that Cdk5-mediated phosphorylation of Shank3 plays a critical role in maintaining dendritic spine morphology and synaptic plasticity. Our collective results demonstrate a central role for Cdk5 in regulating both presynaptic and postsynaptic functions and provide better insight into how specific targets of Cdk5 can impact a general mechanism underlying synaptic transmission, synaptic plasticity, and cognitive function.by Susan C. Su.Ph.D.in Neuroscienc

Forebrain-specific deletion of Cdk5 in pyramidal neurons results in mania-like behavior and cognitive impairment

Cyclin-dependent kinase 5 (Cdk5) is associated with synaptic plasticity and cognitive function. Previous reports have demonstrated that Cdk5 is necessary for memory formation, although others have reported Cdk5 conditional knockout mouse models exhibiting enhanced learning and memory. Furthermore, how Cdk5 acts in specific cell populations to affect behavior and cognitive outcomes remains unclear. Here we conduct a behavioral characterization of a forebrain-specific Cdk5 conditional knockout mouse model under the αCaMKII promoter, in which Cdk5 is ablated in excitatory pyramidal neurons of the forebrain. The Cdk5 conditional knockouts exhibit hyperactivity in the open field, reduced anxiety, and reduced behavioral despair. Moreover, the Cdk5 conditional knockouts also display impaired spatial learning in the Morris water maze and are severely impaired in contextual fear memory, which correspond to deficits in synaptic transmission. Remarkably, the hyperactivity of the Cdk5 conditional knockouts can be ameliorated by the administration of lithium chloride, an inhibitor of GSK3β signaling. Collectively, our data reveal that Cdk5 ablation from forebrain excitatory neurons results in deleterious effects on emotional and cognitive behavior and highlight a key role for Cdk5 in regulating the GSK3β signaling pathway.National Institutes of Health (U.S.) (Grant T32 MH074249)National Institutes of Health (U.S.) (Grant R01 NS051874

Loss of Protein Arginine Methyltransferase 8 Alters Synapse Composition and Function, Resulting in Behavioral Defects

Diverse molecular mechanisms regulate synaptic composition and function in the mammalian nervous system. The multifunctional protein arginine methyltransferase 8 (PRMT8) possesses both methyltransferase and phospholipase activities. Here we examine the role of this neuron-specific protein in hippocampal plasticity and cognitive function. PRMT8 protein localizes to synaptic sites, and conditional whole-brain Prmt8 deletion results in altered levels of multiple synaptic proteins in the hippocampus, using both male and female mice. Interestingly, these altered protein levels are due to post-transcriptional mechanisms as the corresponding mRNA levels are unaffected. Strikingly, electrophysiological recordings from hippocampal slices of mice lacking PRMT8 reveal multiple defects in excitatory synaptic function and plasticity. Furthermore, behavioral analyses show that PRMT8 conditional knock-out mice exhibit impaired hippocampal-dependent fear learning. Together, these findings establish PRMT8 as an important component of the molecular machinery required for hippocampal neuronal function

Age as a predisposing factor of respiratory alkalosis in accidental carbon monoxide poisoning

AbstractAimsThe purpose of this study was to determine the frequency of and identify the predisposing factors for respiratory alkalosis in patients with accidental carbon monoxide (CO) poisoning.MethodsPatients presenting to the emergency department with accidental CO poisoning were retrospectively identified and divided into Group A (no respiratory alkalosis) and Group B (respiratory alkalosis). Charts were reviewed for neurologic status, various demographic factors, and laboratory data.ResultsA total 96 patients, 37 (38.5%) men and 59 (61.5%) women, were identified. Of these, the 58 (60.4%) patients without respiratory alkalosis were placed in Group A and the 38 (39.6%) patients with respiratory alkalosis were placed in Group B. Independent multivariate predictors of CO poisoning presenting with respiratory alkalosis were age [odds ratio (OR), 1.04; 95% confidence interval (CI), 1.01–1.08] and respiratory rate (OR, 1.16; 95% CI, 1.01–1.33). The rates of respiratory alkalosis in patients younger than 15 years, 15–29 years, 30–44 years, 45–59 years, and older than 59 years were 17.4%, 32.4%, 51.9%, 75%, and 75%, respectively (p<0.01).ConclusionsRespiratory alkalosis in the patients with CO poisoning is not an uncommon finding, and as age increases, the percentage becomes higher. When emergency physicians are faced with patients presenting with respiratory alkalosis of undetermined cause, CO poisoning should be taken into consideration, especially in the elderly

Acute necrotizing eosinophilic myocarditis in a young woman

Abstract Eosinophilic myocarditis is recognized by severe heart failure and marked eosinophilia infiltration resulting from different etiologies. Acute necrotizing eosinophilic myocarditis, the initial presentation of the disease, is rare and often fatal, with unique echocardiographic pictures, and followed by endocardial thrombosis and chronic endomyocardial fibrosis. We report a young female with acute lymphoblastic leukemia who presented fever and acute heart failure syndrome. The echocardiography showed severe left ventricle diastolic dysfunction with preserved ejection fraction. Systemic eosinophilia and the unique echocardiographic images made the diagnosis of acute necrotizing eosinophilic myocarditis. The patient survived after intensive cytotoxic chemotherapy including high-dose steroid

Age-Heterogeneity in Marine Sediments Revealed by Three-Dimensional High-Resolution Radiocarbon Measurements

Marine sedimentary archives are routinely used to reconstruct past environmental changes. In many cases, bioturbation and sedimentary mixing affect the proxy time-series and the age-depth relationship. While idealized models of bioturbation exist, they usually assume homogeneous mixing, thus that a single sample is representative for the sediment layer it is sampled from. However, it is largely unknown to which extent this assumption holds for sediments used for paleoclimate reconstructions. To shed light on 1) the age-depth relationship and its full uncertainty, 2) the magnitude of mixing processes affecting the downcore proxy variations, and 3) the representativity of the discrete sample for the sediment layer, we designed and performed a case study on South China Sea sediment material which was collected using a box corer and which covers the last glacial cycle. Using the radiocarbon content of foraminiferal tests as a tracer of time, we characterize the spatial age-heterogeneity of sediments in a three-dimensional setup. In total, 118 radiocarbon measurements were performed on defined small- and large-volume bulk samples ( ∼ 200 specimens each) to investigate the horizontal heterogeneity of the sediment. Additionally, replicated measurements on small numbers of specimens (10 × 5 specimens) were performed to assess the heterogeneity within a sample volume. Visual assessment of X-ray images and a quantitative assessment of the mixing strength show typical mixing from bioturbation corresponding to around 10 cm mixing depth. Notably, our 3D radiocarbon distribution reveals that the horizontal heterogeneity (up to 1,250 years), contributing to the age uncertainty, is several times larger than the typically assumed radiocarbon based age-model error (single errors up to 250 years). Furthermore, the assumption of a perfectly bioturbated layer with no mixing underneath is not met. Our analysis further demonstrates that the age-heterogeneity might be a function of sample size; smaller samples might contain single features from the incomplete mixing and are thus less representative than larger samples. We provide suggestions for future studies, optimal sampling strategies for quantitative paleoclimate reconstructions and realistic uncertainty in age models, as well as discuss possible implications for the interpretation of paleoclimate records

Prenatal diagnosis of a de novo 9p terminal chromosomal deletion in a fetus with major congenital anomalies

AbstractObjectiveWe describe a prenatal ultrasonography diagnosis of omphalocele and symbrachydactyly in a fetus and review the literature on prenatal diagnosis of 9p terminal chromosomal deletions.Case reportA 31-year-old woman (gravida 3, para 1) was referred for genetic counseling because a fetal omphalocele had been detected. Prenatal ultrasonography at 17+ weeks of gestational age revealed a singleton female fetus with biometry equivalent to 18 weeks with an omphalocele. In addition, symbrachydactyly was also noted in the right arm; the wrist bones as well as the metacarpals were missing. A chromosomal study was arranged for a congenital anomaly involving omphalocele. We obtained Giemsa-banded chromosomes from fetal tissue cells, and an abnormal male karyotype with a terminal deletion of the short arm of chromosome 9 at band 9p13 was noted. After delivery, the fetus showed omphalocele, symbrachydactyly, trigonocephaly, sex reversal, a long philtrum, low-set ears, telecanthus, and a frontal prominence.ConclusionPrenatal diagnosis of abnormal ultrasound findings with omphalocele and symbrachydactyly should include the differential diagnosis of a chromosome 9p deletion

Diagnostic Value of I-131 NP-59 SPECT/CT Scintigraphy in Patients with Subclinical or Atypical Features of Primary Aldosteronism

Accumulating evidence has shown the adverse effect of long-term hyperaldosteronism on cardiovascular morbidity that is independent of blood pressure. However, the diagnosis of primary aldosteronism (PA) remains a challenge for patients who present with subtle or atypical features or have chronic kidney disease (CKD). SPECT/CT has proven valuable in the diagnosis of a number of conditions. The aim of this study was to determine the usefulness of I-131 NP-59 SPECT/CT in patients with atypical presentations of PA and in those with CKD. The records of 15 patients with PA were retrospectively analyzed. NP-59 SPECT/CT was able to identify adrenal lesion(s) in CKD patients with suspected PA. Patients using NP-59 SPECT/CT imaging, compared with those not performing this procedure, significantly featured nearly normal serum potassium levels, normal aldosterone-renin ratio, and smaller adrenal size on CT and pathological examination and tended to feature stage 1 hypertension and non-suppressed plasma renin activity. These findings show that noninvasive NP-59 SPECT/CT is a useful tool for diagnosis in patients with subclinical or atypical features of PA and those with CKD

Sedimentological characteristics and seafloor failure offshore SW Taiwan

In this study, analysis results reveal two main deposition zones are located at the flank of upper Gaoping Submarine Canyon and Lower Fangliao Basin offshore SW Taiwan. The non-event related sediments deposited in past 150 years (i.e., 632 Mt km-2) was delivered and transported from Gaoping River by suspension process with tides and coastal currents and gradually spread out offshore. Meanwhile, the total mass of accumulation sediments is 1922 Mt km-2, accounting for 40% Gaoping Riverâs sediment load and suggesting that the deposition process is mainly controlled by natural hazards. Sedimentation rates in much of the study area, except in the main deposition zones, are less than 0.5 cm yr-1 (5 m kyr-1). Compared with the studies at the instability seafloor caused by high sedimentation rates (~30 m kyr-1), the offshore southwestern Taiwan is relatively stable. In this study, we also discovered a series of sediment waves located on the upper continental slope between Gaoping and Fangliao Submarine Canyons, which is related to the creeping process on seafloor. In summary, our results reveal the fluid activities, existence of weak layers and earthquake triggering are potential factors which might induced seafloor failures offshore southwestern Taiwan

Clinical application of tumor volume in advanced nasopharyngeal carcinoma to predict outcome

<p>Abstract</p> <p>Background</p> <p>Current staging systems have limited ability to adjust optimal therapy in advanced nasopharyngeal carcinoma (NPC). This study aimed to delineate the correlation between tumor volume, treatment outcome and chemotherapy cycles in advanced NPC.</p> <p>Methods</p> <p>A retrospective review of 110 patients with stage III-IV NPC was performed. All patients were treated first with neoadjuvant chemotherapy, then concurrent chemoradiation, and followed by adjuvant chemotherapy as being the definitive therapy. Gross tumor volume of primary tumor plus retropharyngeal nodes (GTVprn) was calculated to be an index of treatment outcome.</p> <p>Results</p> <p>GTVprn had a close relationship with survival and recurrence in advanced NPC. Large GTVprn (≧13 ml) was associated with a significantly poorer local control, lower distant metastasis-free rate, and poorer survival. In patients with GTVprn ≧ 13 ml, overall survival was better after ≧4 cycles of chemotherapy than after less than 4 cycles.</p> <p>Conclusions</p> <p>The incorporation of GTVprn can provide more information to adjust treatment strategy.</p