Coffin-Lowry Syndrome Research Articles

The natural course of newborns with transient congenital hypothyroidism.

The incidence of congenital hypothyroidism (CH) has increased worldwide over the last decades, mainly due to the lowering of screening thresholds, resulting in the increased identification of newborns with transient CH. Several studies have reported the prevalence and the predictive parameters of transient CH, but reports on the long-term outcome are rare. This study aimed to assess the long-term course of neonates with transient CH. Neonates diagnosed with transient and permanent CH between the years 1998 and 2018 at the Pediatric Endocrine Institute of Ha'Emek Medical Center were enrolled in the study. Data were retrieved retrospectively from medical files. A total of 76 newborns (45M, 59%) with transient CH and 53 (25M, 47%) with permanent CH were included in the study. The major causes of transient CH were prematurity (29%) and subclinical hypothyroidism (30%). During retrospective follow-ups of up to 23 years, reinitiation of levothyroxine therapy was not required, apart from four patients with underlying syndromic etiologies. Neurodevelopmental impairment occurred in 16% of children with transient CH compared with 29.4% in the permanent CH group. Transient CH is frequent among preterm infants but is generally limited to infancy. Subclinical hypothyroidism frequently presents as overt hypothyroidism at birth, but in most cases, the requirement for levothyroxine supplemental therapy is limited to the first years of life, suggesting that long-term follow-up of thyroid function tests may be unnecessary for non-syndromic children. The high rate of neurodevelopmental impairment in newborns with transient CH emphasizes the need for neurodevelopmental monitoring in these patients. A high rate of transient CH has been identified over the past decades following the lowering of TSH screening thresholds. The long-term outcome of transient CH has been evaluated in a few studies with inconclusive results. In the current study, we assessed the long-term outcomes of transient CH for up to 23 years. We found that 29% of cases were attributed to prematurity and 30% to subclinical hypothyroidism. No morphological anomalies were identified. Only syndromic patients (three with Down syndrome and one with Coffin-Lowry syndrome) required levothyroxine supplemental therapy at the time of the study, indicating that long-term thyroid function monitoring may be unnecessary. The high prevalence of neurodevelopmental impairment suggests the need for close neurodevelopmental monitoring in this population.

Airway management of a patient with coffin-lowry syndrome: a case report

Coffin-Lowry Syndrome (CLS) is a rare X-linked genetic disorder characterized by growth delays, facial dysmorphisms, and intellectual disabilities. Currently, there are limited published case reports regarding the anesthetic management of patients with CLS. Managing anesthesia for CLS patients can be complex due to difficult airway management. In this case report, we present a patient with CLS who underwent surgical intervention, highlighting the anesthetic considerations encountered throughout the perioperative period. We aim to summarize the difficulties involved in anesthetic management of rare conditions like CLS to improve clinical outcomes for affected individuals.

Identification of RSK substrates using an analog-sensitive kinase approach

The p90 ribosomal S6 kinases (RSK) family of serine/threonine kinases comprises four isoforms (RSK1-4) that lie downstream of the ERK1/2 mitogen-activated protein kinase (MAPK) pathway. RSKs are implicated in fine tuning of cellular processes such as translation, transcription, proliferation, and motility. Previous work showed that pathogens such as Cardioviruses could hijack any of the four RSK isoforms to inhibit PKR activation or to disrupt cellular nucleocytoplasmic trafficking. In contrast, some reports suggest non-redundant functions for distinct RSK isoforms, whereas Coffin-Lowry syndrome has only been associated with mutations in the gene encoding RSK2. In this work, we used the analog-sensitive kinase strategy to ask whether the cellular substrates of distinct RSK isoforms differ. We compared the substrates of two of the most distant RSK isoforms: RSK1 and RSK4. We identified a series of potential substrates for both RSKs in cells, and validated RanBP3, PDCD4, IRS2 and ZC3H11A as substrates of both RSK1 and RSK4, and SORBS2 as an RSK1 substrate. In addition, using mutagenesis and inhibitors, we confirmed analog-sensitive kinase data showing that endogenous RSKs phosphorylate TRIM33 at S1119. Our data thus identify a series of potential RSK substrates and suggest that the substrates of RSK1 and RSK4 largely overlap and that the specificity of the various RSK isoforms likely depends on their cell- or tissue-specific expression pattern.

An unexpected presentation of very severe hypertriglyceridemia in a boy with Coffin-Lowry syndrome: a case report

BackgroundCoffin-Lowry syndrome (CLS) is a rare X-linked condition with intellectual disability, growth retardation, characteristic facies and skeletal anomalies. To date, hypertriglyceridemia has not been reported in literature to be associated with CLS.Case PresentationHerein, we report a case of very severe hypertriglyceridemia 32 mmol/L (2834 mg/dL) detected incidentally at three months old in an otherwise well boy born late preterm with intrauterine growth restriction, when he presented with lipaemic plasma. He was later diagnosed with CLS. No pathogenic mutations were found for hypertriglyceridemia, and no secondary causes could explain his very severe hypertriglyceridemia.ConclusionsThe very severe hypertriglyceridemia in this case may appear to be a serious presentation of an unrecognised clinical feature of CLS, further expanding its phenotype.

P-708 Establishment of linkage phase, using Oxford Nanopore Technologies, for Preimplantation Genetic Testing of Coffin-Lowry syndrome with a de novo RPS6KA3 mutation

Abstract Study question There was a challenge to establishing haplotype for PGT in the family with de novo mutation because of the lack of information from affected members. Summary answer The ONT platform combined with MARSALA method can be used to perform PGT for DNM patients without the need for other samples as a reference. What is known already The proband was a 31-year-old female who was born with mental retardation and language delay. On physical examination, she was found to have distinctive Coffin-Lowry Syndrome features, such as distance between the eyes and low nasal bridge. However, the proband’s parents did not show any abnormalities. The couple underwent genetic counseling and whole-exome sequencing (WES). The results showed that a frameshift mutation (c.1496delG, p.Gly499Valfs*25) was identified in the RPS6KA3 gene, with a true mutation in the proband but no mutations in the parents. Study design, size, duration A couple requested genetic counseling at the reproductive center of Zhongshan Boai Hospital and underwent whole-exome sequencing (WES) in 2019. The proband then underwent PGT with Oxford Nanopore Technologies (ONT) and the MARSALA platform to block the transmission of the pathogenic mutation to her offspring in 2022. Participants/materials, setting, methods The proband underwent PGT to block the transmission of the pathogenic mutation to her offspring.We used long-read sequencing on the ONT platform to directly detect the mutation and nearby SNPs for construction of the haplotype in PGT. The MARSALA method was used to detect both the SNP-based haplotype and chromosome copy number variations in each blastocyst. Finally, a normal embryo was selected by comparison to the haplotype of the proband and transferred into the uterus. Main results and the role of chance Using WES, we found the novel, heterozygous, pathogenic c.1496delG (p.Gly499Valfs*25) mutation of the RPS6KA3 gene in the proband. The SNP-based haplotype that was linked to the pathogenic mutation site was successfully established in the proband, without the need for other family members to be tested with ONT. Eight blastocysts were biopsied to perform PGT and were assessed with a haplotype linkage analysis (30 SNP sites selected), to give results that were consistent with direct mutation detection using Sanger sequencing. The results of PGT showed that three of the eight blastocysts were normal, without the DNM. Moreover, the patient had a successful pregnancy, after transfer of a normal blastocyst into the uterus, and delivered a healthy baby. Limitations, reasons for caution This strategy has only been applied to one case and more cases with de novo mutaition are needed to prove the feasibility of this strategy for PGT-M. Wider implications of the findings This study is the first report of a de novo RPS6KA3 c.1496delG mutation in patient with CLS, which can expands the RPS6KA3 mutation spectrum and also provides a new strategy based on ONT and MARSALA to perform PGT-M with DNMs without the need for a pedigree sample as a reference. Trial registration number Not applicable

Delayed postnatal brain development and ontogenesis of behavior and cognition in a mouse model of intellectual disability

Intellectual disability (ID) is a neurodevelopmental disorder associated with impaired cognitive and adaptive behaviors and represents a major medical issue. Although ID-patients develop behavioral problems and are diagnosed during childhood, most behavioral studies in rodent models have been conducted in adulthood, missing precocious phenotypes expressed during this critical time-window characterized by intense brain plasticity. Here, we selectively assessed postnatal ontogenesis of behavioral and cognitive processes, as well as postnatal brain development in the male Rsk2-knockout mouse model of the Coffin-Lowry syndrome, an X-linked disorder characterized by ID and neurological abnormalities. While Rsk2-knockout mice were born healthy, a longitudinal MRI study revealed a transient secondary microcephaly and a persistent reduction of hippocampal and cerebellar volumes. Specific behavioral parameters from postnatal day 4 (P4) unveiled delayed acquisition of sensory-motor functions and alterations of spontaneous and cognitive behaviors during adolescence, which together, represent hallmarks of neurodevelopmental disorders. Together, our results suggest for the first time that RSK2, an effector of the MAPK signaling pathways, plays a crucial role in brain and cognitive postnatal development. This study also provides new relevant measures to characterize postnatal cognitive development of mouse models of ID and to design early therapeutic approaches.

A rare case of Coffin–Lowry syndrome accompanied by a copper-beaten skull appearance

Coffin-Lowry syndrome (CLS), usually a result of loss-of-function mutations in the RPS6KA3 gene located at Xp22.2, is a very rare genetic condition. It is associated with different phenotypes, including dysmorphic facial features, neuro-developmental impairment, short stature, and skeletal deformities. Here we describe a four-year-old boy who had distinct clinical features of CLS: moderate mental and motor retardation, brachycephaly, microcephaly, hypertelorism, low-set and prominent ears, down- slanted palpebral fissures, a depressed nasal bridge with thick nasal alae and septum, a high-arched palate, widely spaced teeth, and retrognathia. Genetic analysis revealed a pathogenic variant in the RPS6KA3 gene, NM_004586.3: exon 22: c.2186G>A: (p.Arg729Gln). His healthy mother was a heterozygous carrier of the variant. In addition to the clinical findings, the patient’s X-ray revealed a very rare feature of a copper-beaten skull appearance. The link between CLS and a copper-beaten skull has never been reported before. This case demonstrates the variability in presentation of CLS and signifies the association of a rare radiographic finding of copper-beaten skull with CLS. Based on this case, we recommend screening skull radiographs at the clinic for copper-beaten skulls in patients with CLS.

Establishment of linkage phase, using Oxford Nanopore Technologies, for preimplantation genetic testing of Coffin-Lowry syndrome with a de novo RPS6KA3 mutation.

Background: This study aimed to perform preimplantation genetic testing (PGT) for a female Coffin-Lowry Syndrome (CLS) patient with a de novo mutation (DNM) in RPS6KA3. It was challenging to establish the haplotype in this family because of the lack of information from affected family members. Hence, we explored a new and reliable strategy for the detection of the DNM in PGT, using Oxford Nanopore Technologies (ONT) and the MARSALA platform. Methods: We performed whole-exome sequencing (WES) on the proband and confirmed the pathogenic mutation by Sanger sequencing. The proband then underwent PGT to prevent the transmission of the pathogenic mutation to her offspring. We diverged from the conventional methods and used long-read sequencing (LRS) on the ONT platform to directly detect the mutation and nearby SNPs, for construction of the haplotype in the preclinical phase of PGT. In the clinical phase of embryo diagnosis, the MARSALA method was used to detect both the SNP-based haplotype and chromosome copy number variations (CNVs), in each blastocyst. Finally, a normal embryo was selected by comparison to the haplotype of the proband and transferred into the uterus. Sanger sequencing and karyotyping were performed by amniocentesis, at 17weeks of gestation, to confirm the accuracy of PGT. Results: Using WES, we found the novel, heterozygous, pathogenic c.1496delG (p.Gly499Valfs*25) mutation of RPS6KA3 in the proband. The SNP-based haplotype that was linked to the pathogenic mutation site was successfully established in the proband, without the need for other family members to be tested with ONT. Eight blastocysts were biopsied to perform PGT and were assessed with a haplotype linkage analysis (30 SNP sites selected), to give results that were consistent with direct mutation detection using Sanger sequencing. The results of PGT showed that three of the eight blastocysts were normal, without the DNM. Moreover, the patient had a successful pregnancy, after transfer of a normal blastocyst into the uterus, and delivered a healthy baby. Conclusion: The ONT platform, combined with the MARSALA method, can be used to perform PGT for DNM patients without the need for other samples as a reference.

Defective synaptic plasticity in a model of Coffin-Lowry syndrome is rescued by simultaneously targeting PKA and MAPK pathways.

Empirical and computational methods were combined to examine whether individual or dual-drug treatments can restore the deficit in long-term synaptic facilitation (LTF) of the Aplysia sensorimotor synapse observed in a cellular model of Coffin-Lowry syndrome (CLS). The model was produced by pharmacological inhibition of p90 ribosomal S6 kinase (RSK) activity. In this model, coapplication of an activator of the mitogen-activated protein kinase (MAPK) isoform ERK and an activator of protein kinase A (PKA) resulted in enhanced phosphorylation of RSK and enhanced LTF to a greater extent than either drug alone and also greater than their additive effects, which is termed synergism. The extent of synergism appeared to depend on another MAPK isoform, p38 MAPK. Inhibition of p38 MAPK facilitated serotonin (5-HT)-induced RSK phosphorylation, indicating that p38 MAPK inhibits activation of RSK. Inhibition of p38 MAPK combined with activation of PKA synergistically activated both ERK and RSK. Our results suggest that cellular models of disorders that affect synaptic plasticity and learning, such as CLS, may constitute a useful strategy to identify candidate drug combinations, and that combining computational models with empirical tests of model predictions can help explain synergism of drug combinations.

Premature Loss of Deciduous Teeth as a Symptom of Systemic Disease: A Narrative Literature Review.

Background: Premature loss of primary teeth can occur as a consequence of dental trauma, neonatal tooth extraction, early childhood caries, or periodontal problems, or it can be a manifestation of systemic disease. This review aims to present systemic disorders that can lead to premature loss of deciduous teeth in children and to provide a comprehensive resource for clinical practice for both physicians and dentists. Methods: This study is a narrative review of original studies and case reports published in English and Polish between 1957 and 2021 that was conducted by searching electronic scientific resources: PubMed, Google Scholar, Web of Science, and Science Direct. The schema of the qualification process is represented by a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). In total, 196 articles were identified; after provisional assessment of the titles and abstracts by two reviewers, 46 were found to be relevant to the topic, including 1 review, 16 original papers, and 27 case reports regarding systemic disease resulting in premature tooth loss. Results: In this study, 16 systemic diseases were linked to premature primary tooth loss in children: Papillon–Lefèvre syndrome, mucocutaneous dyskeratosis, Coffin–Lowry syndrome, congenital adrenal hyperplasia, Langerhans cell histiocytosis, cherubism, hypophosphatasia, acatalasia, Chediak–Higashi syndrome, cyclic neutropenia, erythromelalgia, Down syndrome, Hajdu–Cheney syndrome, short bowel syndrome, leukocyte adhesion deficiency type 1 (LAD-1), and Wiedemann–Steiner syndrome (WSS).

Short Bones, Renal Stones, and Diagnostic Moans: Hypercalcemia in a Girl Found to Have Coffin-Lowry Syndrome

Pathogenic variants in RPS6KA3 are associated with Coffin-Lowry syndrome (CLS), an X-linked semidominant disorder characterized by intellectual disability, stimulus-induced drop attacks, distinctive facial features, progressive kyphoscoliosis, and digit anomalies in hemizygous males. Heterozygous females may also have features of CLS; however, there can be considerable phenotypic variation, often attributed to ratios of X-inactivation in various tissue types. Although skeletal anomalies and short stature are hallmarks of CLS, hypercalcemia has not been reported. Here we describe a 30-month-old girl with gross motor delays, short stature, dysmorphic features, bilateral duplicated renal collecting systems, and no family history of hypercalcemia who required multiple admissions for idiopathic hypercalcemia necessitating bisphosphonate infusions at 12.5 and 15 months of age. A maternally inherited likely-pathogenic variant in RPS6KA3 was identified by trio exome sequencing, consistent with the diagnosis of CLS in the proband and her mother. Maternal history was notable only for decreased height compared to first-degree relatives, bilateral genu valgum, and a bicornuate uterus; she was later found to also have a partially duplicated left renal collecting system. Subsequent X-inactivation studies in blood aligned with the phenotypic variation between mother and daughter. Although hypercalcemia is not a reported feature in CLS, there is evidence of interrupted osteoblast differentiation, providing a potential mechanism for hypercalcemia in this genetic condition. The hypercalcemia in this case may represent a severe presentation of an unrecognized clinical feature in CLS that resolves with age. This case further highlights the intrafamilial phenotypic variation of CLS among females, suggesting X-inactivation as the underlying mechanism, and demonstrates the value of exome sequencing in patients for whom a genetic disorder is highly suspected but not identified despite thorough evaluation.

Postmortem findings in the Coffin-Lowry Syndrome

The Coffin-Lowry Syndrome (CLS) is a congenital disorder that can be recognized by retarded growth and development, the characteristic appearance of the face and hands, and often by the typical deformities of the back and chest; there are many other anomalies. The history of the syndrome is reviewed, noting the x-linked semidominant pattern of inheritance, and two autopsies are presented and compared with the three autopsy reports that have been published previously. The five young patients died at ages between 18 to 28 years of advancing pneumonia, aspiration of food into the trachea, or postoperative complications. There were lesions or abnormalities in the heart, brain, lungs, liver, skeleton, kidneys, intestines, and other organs. Molecular geneticists have located the CLS gene or Rsk-2 gene at Xp22.2 and demonstrated that it works by influencing the activation of other genes. The “monopolygenic” pattern may help to explain the large number of seemingly unrelated abnormalities that make up this syndrome.

Identification of a New Mutation in RSK2, the Gene for Coffin–Lowry Syndrome (CLS), in Two Related Patients with Mild and Atypical Phenotypes

Background: Coffin–Lowry syndrome (CLS) is a syndromic form of X-linked intellectual disability, in which specific associated facial, hand, and skeletal abnormalities are diagnostic features. Methods: In the present study, an unreported missense genetic variant of the ribosomal S6 kinase 2 (RSK2) gene has been identified, by next-generation sequencing, in two related males with two different phenotypes of intellectual disability (ID) and peculiar facial dysmorphisms. We performed functional studies on this variant and another one, already reported in the literature, involving the same amino acid residue but, to date, without an efficient characterization. Results: Our study demonstrated that the two variants involving residue 189 significantly impaired its kinase activity. Conclusions: We detected a loss-of-function RSK2 mutation with loss in kinase activity in a three-generation family with an X-linked ID.

Quantitative description of the interactions among kinase cascades underlying long-term plasticity of Aplysia sensory neurons

Kinases play critical roles in synaptic and neuronal changes involved in the formation of memory. However, significant gaps exist in the understanding of how interactions among kinase pathways contribute to the mechanistically distinct temporal domains of memory ranging from short-term memory to long-term memory (LTM). Activation of protein kinase A (PKA) and mitogen-activated protein kinase (MAPK)—ribosomal S6 kinase (RSK) pathways are critical for long-term enhancement of neuronal excitability (LTEE) and long-term synaptic facilitation (LTF), essential processes in memory formation. This study provides new insights into how these pathways contribute to the temporal domains of memory, using empirical and computational approaches. Empirical studies of Aplysia sensory neurons identified a positive feedforward loop in which the PKA and ERK pathways converge to regulate RSK, and a negative feedback loop in which p38 MAPK inhibits the activation of ERK and RSK. A computational model incorporated these findings to simulate the dynamics of kinase activity produced by different stimulus protocols and predict the critical roles of kinase interactions in the dynamics of these pathways. These findings may provide insights into the mechanisms underlying aberrant synaptic plasticity observed in genetic disorders such as RASopathies and Coffin-Lowry syndrome.

Acute Transient Central Diabetes Insipidus: A Rare Case of DI Secondary to Vasopressin Withdrawal

Introduction: Transient Central Diabetes Insipidus (tCDI) induced by vasopressin withdrawal is a rare condition which is possibly under recognized. It occurs in very sick, often critically ill patients and usually complicates an already complex clinical picture, so early recognition and treatment are critical to reduce morbidity.Case Description: A 47-y/o male with a PMH of Coffin Lowry syndrome, atrial fibrillation, and GERD presented with abdominal pain and flu like symptoms. His home medications were metoprolol, loratadine and colestipol. Work up revealed bowel perforation for which he was taken to the OR for repair. Intraoperatively he developed septic shock requiring pressor support with norepinephrine and vasopressin. He was weaned off norepinephrine on post-op day (POD)1, and vasopressin on POD 2. Approximately three hours after withdrawal of vasopressin support his urine output increased dramatically up to a peak of 350 cc/hour with a recorded 24hr urine volume of >5L. Concurrently, his serum sodium was found to have increased from 147 mmol/L to 173 mmol/L (n 135-145) over the course of 13 hours. Clinically, he became increasingly lethargic with abnormal eye movements. His sodium did not improve with fluid management with D5W. His other laboratory values included a urine osmolality of 141 mOsm/kg, urine sodium of 60 mmol/L and a peak serum sodium of 177mmol/L. He was administered 1mcg desmopressin and his D5W rate was increased. His urine output dropped gradually to ~150cc/hr, his serum sodium level started to trend down to 168 mmol/L and his urine osmolality increased to 439 mOsm/kg five hours after desmopressin administration, with improvement in mental status. The patient received a total of two doses of desmopressin and continued support with IV fluids. His sodium eventually normalized, and his polyuria did not return.Discussion: This patient’s clinical picture is consistent with tCDI secondary to discontinuation of vasopressin. Transient Central diabetes insipidus due to vasopressin withdrawal is a phenomenon that is not well understood, but there is a strong male preponderance, and it tends to occur more commonly in patients with underlying neurological conditions, as did our patient. Current proposed mechanisms include decreased production and release of exogenous ADH due to negative feedback, down regulation of the V2 receptors, and hypoperfusion to the posterior pituitary. This condition deserves more investigation to better understand the incidence, risk factors and pathophysiological mechanisms.

EP180 - Variable expressivity of Coffin Lowry syndrome in a female patient: a case report

eP180 - Variable expressivity of Coffin Lowry syndrome in a female patient: a case report

Modeling suggests combined-drug treatments for disorders impairing synaptic plasticity via shared signaling pathways.

Genetic disorders such as Rubinstein-Taybi syndrome (RTS) and Coffin-Lowry syndrome (CLS) cause lifelong cognitive disability, including deficits in learning and memory. Can pharmacological therapies be suggested that improve learning and memory in these disorders? To address this question, we simulated drug effects within a computational model describing induction of late long-term potentiation (L-LTP). Biochemical pathways impaired in these and other disorders converge on a common target, histone acetylation by acetyltransferases such as CREB binding protein (CBP), which facilitates gene induction necessary for L-LTP. We focused on four drug classes: tropomyosin receptor kinase B (TrkB) agonists, cAMP phosphodiesterase inhibitors, histone deacetylase inhibitors, and ampakines. Simulations suggested each drug type alone may rescue deficits in L-LTP. A potential disadvantage, however, was the necessity of simulating strong drug effects (high doses), which could produce adverse side effects. Thus, we investigated the effects of six drug pairs among the four classes described above. These combination treatments normalized impaired L-LTP with substantially smaller individual drug 'doses'. In addition three of these combinations, a TrkB agonist paired with an ampakine and a cAMP phosphodiesterase inhibitor paired with a TrkB agonist or an ampakine, exhibited strong synergism in L-LTP rescue. Therefore, we suggest these drug combinations are promising candidates for further empirical studies in animal models of genetic disorders that impair histone acetylation, L-LTP, and learning.

Prenatal diagnosis and genetic analysis of a fetus with Xp22.12 microduplication

To provide prenatal diagnosis for a pregnant women carrying a chromosome translocations using single nucleotide polymorphism array (SNP-array). The fetus and its parents were subjected to chromosome karyotyping and SNP array analysis. A Xp22.12 microduplication was identified in the fetus with a size of 496.3 kb. Search of literature and database indicated the microduplication to be variant of unclear significance. The phenotypically normal mother has carried a 505.8 kb duplication at the same position. The father was normal for the testing. The couple decided to continue with the pregnancy and gave birth to a healthy girl at full-term. No abnormality was found during the follow-up. The Xp22.12 microduplication encompassed part of RPS6KA3 gene, which shows various features of Coffin-Lowry syndrome. Female with Xp22.12 microduplications may be asymptomatic carriers due to X chromosome inactivation. Our case may provide data for delineating the phenotype-genotype correlation of Xp22.12 microduplication.

伴有色素减退斑的Coffin-Lowry综合征一例

伴有色素减退斑的Coffin-Lowry综合征一例

Role of p90 ribosomal S6 kinase in long-term synaptic facilitation and enhanced neuronal excitability

Multiple kinases converge on the transcription factor cAMP response element-binding protein (CREB) to enhance the expression of proteins essential for long-term synaptic plasticity and memory. The p90 ribosomal S6 kinase (RSK) is one of these kinases, although its role is poorly understood. The present study exploited the technical advantages of the Aplysia sensorimotor culture system to examine the role of RSK in long-term synaptic facilitation (LTF) and long-term enhancement of neuronal excitability (LTEE), two correlates of long-term memory (LTM). Inhibition of RSK expression or RSK activity both significantly reduced CREB1 phosphorylation, LTF, and LTEE, suggesting RSK is required for learning-related synaptic plasticity and enhancement in neuronal excitability. In addition, knock down of RSK by RNAi in Aplysia sensory neurons impairs LTF, suggesting that this may be a useful single-cell system to study aspects of defective synaptic plasticity in Coffin-Lowry Syndrome (CLS), a cognitive disorder that is caused by mutations in rsk2 and associated with deficits in learning and memory. We found that the impairments in LTF and LTEE can be rescued by a computationally designed spaced training protocol, which was previously demonstrated to augment normal LTF and LTM.