Dopaminergic loss of cyclin-dependent kinase-like 5 recapitulates methylphenidate-remediable hyperlocomotion in mouse model of CDKL5 deficiency disorder

2020 ◽  
Vol 29 (14) ◽  
pp. 2408-2419
Author(s):  
Cian-Ling Jhang ◽  
Hom-Yi Lee ◽  
Jin-Chung Chen ◽  
Wenlin Liao
Keyword(s):  
Movement Control ◽  
Motor Dysfunction ◽  
Signaling Proteins ◽  
Cyclin Dependent Kinase ◽  
Serine Threonine Kinase ◽  
Hyperactivity Disorder ◽  
Dopamine Content ◽  
Therapeutic Development ◽  
Dopamine Signaling ◽  
Core Symptoms

Abstract Cyclin-dependent kinase-like 5 (CDKL5), a serine-threonine kinase encoded by an X-linked gene, is highly expressed in the mammalian forebrain. Mutations in this gene cause CDKL5 deficiency disorder, a neurodevelopmental encephalopathy characterized by early-onset seizures, motor dysfunction, and intellectual disability. We previously found that mice lacking CDKL5 exhibit hyperlocomotion and increased impulsivity, resembling the core symptoms in attention-deficit hyperactivity disorder (ADHD). Here, we report the potential neural mechanisms and treatment for hyperlocomotion induced by CDKL5 deficiency. Our results showed that loss of CDKL5 decreases the proportion of phosphorylated dopamine transporter (DAT) in the rostral striatum, leading to increased levels of extracellular dopamine and hyperlocomotion. Administration of methylphenidate (MPH), a DAT inhibitor clinically effective to improve symptoms in ADHD, significantly alleviated the hyperlocomotion phenotype in Cdkl5 null mice. In addition, the improved behavioral effects of MPH were accompanied by a region-specific restoration of phosphorylated dopamine- and cAMP-regulated phosphoprotein Mr 32 kDa, a key signaling protein for striatal motor output. Finally, mice carrying a Cdkl5 deletion selectively in DAT-expressing dopaminergic neurons, but not dopamine receptive neurons, recapitulated the hyperlocomotion phenotype found in Cdkl5 null mice. Our findings suggest that CDKL5 is essential to control locomotor behavior by regulating region-specific dopamine content and phosphorylation of dopamine signaling proteins in the striatum. The direct, as well as indirect, target proteins regulated by CDKL5 may play a key role in movement control and the therapeutic development for hyperactivity disorders.

Disorder-specific alterations of tactile sensitivity in neurodevelopmental disorders

2020 ◽  
Author(s):  
Jason He ◽  
Ericka Wodka ◽  
Mark Tommerdahl ◽  
Richard Edden ◽  
Mark Mikkelsen ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Autism Spectrum ◽  
Typically Developing ◽  
Hyperactivity Disorder ◽  
The Core ◽  
Children With Asd ◽  
Tactile Detection ◽  
Spectrum Disorders ◽  
Sensory Processes ◽  
Core Symptoms

Alterations of tactile processing have long been identified in autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). However, the extent to which these alterations are disorder-specific, rather than disorder-general, and how they relate to the core symptoms of each disorder, remains unclear. We measured and compared tactile detection, discrimination and order judgment thresholds between a large sample of children with ASD, ADHD, ASD + ADHD combined and typically developing controls. The pattern of results suggested that while difficulties with tactile detection and order judgement were more common in children with ADHD, difficulties with tactile discrimination were more common in children with ASD. Strikingly, subsequent correlation analyses found that the disorder-specific alterations suggested by the group comparisons were also exclusively related to the core symptoms of each respective disorder. These results suggest that disorder-specific alterations of lower-level sensory processes exist and are specifically related to higher-level clinical symptoms of each disorder.

Forty years of methylphenidate treatment in Attention-Deficit/Hyperactivity Disorder

2002 ◽  
Vol 6 (1_suppl) ◽  
pp. 17-30 ◽  
Author(s):  
C. K. Conners
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
Attention Deficit ◽  
Drug Effects ◽  
Long Term Effects ◽  
Stimulant Treatment ◽  
Hyperactivity Disorder ◽  
Subject Selection ◽  
Methodological Rigor ◽  
Adolescents And Adults ◽  
Core Symptoms

This paper reviews approximately 40 years of stimulant drug treatment of children with behavior and learning problems. These patients generally fall under the rubric of Attention-Deficit/Hyperactivity Disorder (ADHD), with core symptoms of hyperactivity, impulsivity, and inattention being the most studied and most robust of the targets for stimulant treatment. In addition, the drug effects on other targets, such as cognitive and academic function, are included. The largest selection of studies involves methylphenidate. Both qualitative studies and meta-analytic studies from major reviews are examined. Variations in the methodology of the reviews are described and some of the discrepancies in interpretation examined. Despite wide variations in subject selection, types of trials, degree of methodological rigor, and the decade in which the studies took place, the evidence is remarkably consistent. The overall results suggest significant clinical impact upon the core features of ADHD. More studies of long-term effects and special populations such as older adolescents and adults will be necessary, though existing evidence strongly supports similar findings as for the younger patients with a diagnosis of ADHD.

Age-Related Considerations in the Treatment of ADHD

CNS Spectrums ◽  
2007 ◽  
Vol 12 (S23) ◽  
pp. 10-13 ◽  
Author(s):  
Jeffrey H. Newcorn
Keyword(s):  
Time Management ◽  
Task Completion ◽  
Occupational Performance ◽  
Social Situations ◽  
Attentional Function ◽  
Hyperactivity Disorder ◽  
Age Related ◽  
Adolescents And Adults ◽  
Core Symptoms ◽  
High Degree

Although the symptoms of attention-deficit/hyperactivity disorder (ADHD) can be found in many “normal” people, these symptoms are present to a greater extent in those affected by the disorder. In these patients, ADHD symptoms cause substantial functional impairment. Therefore, the goal of treatment is not simply to reduce core symptoms, but also to decrease the level of impairment caused by these symptoms.Common impairments in adolescents and adults include academic and occupational problems that are particularly evident in the context of tasks requiring a high degree of organization or attentional function. These impairments result in problems related to task completion, prioritizing work and other obligations, and time management, etc. These symptoms often impact successful completion of tasks in school or at work, and can also result in a variety of problems in initiating and managing relationships (Slide 1).Mood and anxiety disorders often co-occur with ADHD in adults. The accumulation of experiences related to impaired academic and/or occupational performance, and or persistent relationship problems, due to the symptoms of ADHD, can lead to either depressed mood or anxiety related to performance and/or social situations. Therefore, in treating adults with ADHD, reduction of those co-occurring symptom presentations is also an important goal.

Neurobiology and Genetics of ADHD in Adults

CNS Spectrums ◽  
2008 ◽  
Vol 13 (S13) ◽  
pp. 5-7 ◽  
Author(s):  
Thomas J. Spencer
Keyword(s):  
Adult Adhd ◽  
Extended Release ◽  
Treatment Strategies ◽  
Stimulant Use ◽  
Hyperactivity Disorder ◽  
Adhd Treatment ◽  
Norepinephrine Reuptake Inhibitor ◽  
Adults And Children ◽  
Core Symptoms ◽  
Adhd Medications

AbstractTreatment of attention-deficit/hyperactivity disorder (ADHD) may positively impact the neurobiology of adult patients with ADHD. Treatment may also minimize impairment from core symptoms and may alter the course of co-morbid disorders such as depression and substance use disorder. However, much of the information on stimulant use in adult ADHD comes from studies conducted in children, and it remains unclear whether there is a difference between children and adults when it comes to the side effects and tolerability of ADHD treatments. It is known that clinical presentation differs between adults and children, with adults demonstrating a higher percentage of mood disorders. Current treatments for adult ADHD include psychosocial therapies and pharmacologic therapies, the latter of which include the stimulants d-methylphenidate extended release (XR), OROS methylphenidate, lisdexamfetamine, and mixed amphetamine salts XR; and the nonstimulant atomoxetine, a selective norepinephrine reuptake inhibitor. There is need for additional study of treatment strategies for adult ADHD. Although all classes of ADHD medications are approved in adults, there are fewer approved formulations for adults than for children. Efficacy in adults is more subjective than in children, which may affect how efficacy rates for adult treatments are calculated. Adults also present a greater diversion risk than children. In addition, there are several new and emerging medication treatments worth considering.This Expert Roundtable Supplement represents part 2 of a 3-part supplement series on adult ADHD led by Lenard A. Adler, MD. In this activity, Thomas J. Spencer, MD, discusses the neurobiology and genetics of adult ADHD; Mark A. Stein, PhD, discusses stimulant therapy; and Jeffrey H. Newcorn, MD, reviews nonstimulants and psychosocial treatments.

Mapping cancer signaling networks by an integrated multiplexed tissue imaging platform

TECHNOLOGY ◽  
2016 ◽  
Vol 04 (03) ◽  
pp. 174-193 ◽  
Author(s):  
Esteban Roberts ◽  
Thomas Jacob ◽  
Karl Garsha ◽  
Damien Ramunno-Johnson ◽  
Franklin Ventura ◽  
...  
Keyword(s):  
Dynamic Range ◽  
Pi3k Pathway ◽  
Tissue Imaging ◽  
Signaling Networks ◽  
Signaling Proteins ◽  
Parametric Image ◽  
Fluorescent Reporters ◽  
Specimen Collection ◽  
Therapeutic Development ◽  
Subcellular Resolution

Aberrant cellular signaling networks are implicated in major diseases including cancer, but are difficult to reliably quantitate, as many signaling proteins are expressed at low abundance and further reduced following specimen collection. MTIP is an integrated tissue-imaging platform that leverages bright, fluorescent reporters and sensitive spectral instrumentation, along with automated staining, image acquisition and non-parametric image analysis, to attain reproducible, multiplexed quantitation of signaling proteins in tissue. MTIP captured the phosphoactivity of six key PI3K/MAPK proteins (pAKTS473, pAKT308, pPRAS40, pS6, peIF4G and pERK1/2) at high precision (coefficient of variation, CV <10%), four-log dynamic range and subcellular resolution. We demonstrated the MTIP platform's capability to capture a diversity of PI3K/MAPK networks present in breast tumors. These protein networks are heterogeneously distributed across the tumor tissue and associated with subgroups of cells and underscore the importance of accessing information about signaling networks in spatially intact tissue. Analysis of PI3K/MAPK networks by hierarchical clustering showed that PI3K/MAPK networks do not strictly correlate with PI3K pathway mutations, also pointing to the value of functional signaling network profiling together with genomic information. MTIP's reliable quantitative capability can be applied to guide therapeutic development and selection in precision medicine.

Students Diagnosed with Attention Deficit Hyperactivity Disorder: Collaborative Strategies for School Counselors

2012 ◽  
Vol 16 (2_suppl) ◽  
pp. 2156759X1201600
Author(s):  
M. Ann Shillingford-Butler ◽  
Lea Theodore
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
School Counselors ◽  
Attention Deficit ◽  
School Setting ◽  
Negative Consequences ◽  
Effective School ◽  
Children With Adhd ◽  
Social And Emotional ◽  
Hyperactivity Disorder ◽  
Core Symptoms

The school setting can be a difficult place for children with attention deficit hyperactivity disorder (ADHD). The core symptoms of ADHD, which include inattention, hyperactivity, and impulsivity, make meeting the curriculum demands of the classroom challenging. That ADHD negatively impacts not only academic performance but also social and emotional functioning is well established (Lee, Lahey, Owens, & Hinshaw, 2008). Given the negative consequences of ADHD, effective school-based interventions are warranted. School counselors are uniquely positioned to implement strategies for children with ADHD to maximize their capacity for learning. This article provides specific strategies that school counselors can provide collaboratively to enhance the academic and social functioning of children with ADHD in school.

Pre-, Peri-, and Post-Natal Risk Factors in ADHD

2021 ◽  
pp. 43-54
Author(s):  
Pangajam Ponnuswamy ◽  
Ann Sarah Paul ◽  
Aneesha Brigitte Jose
Keyword(s):  
Risk Factors ◽  
Attention Deficit Hyperactivity Disorder ◽  
Postnatal Development ◽  
Environmental Risk ◽  
Attention Deficit ◽  
Critical Period ◽  
Neurodevelopmental Disorder ◽  
Therapeutic Interventions ◽  
Hyperactivity Disorder ◽  
Core Symptoms

Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder most commonly found in childhood with its core symptoms manifesting as inattention, impulsiveness, and hyperactivity. As ADHD generates a substantial rate of burden to the society in terms of economic and medical resources used, priority is given to explore the risk factors that contributes towards the multifactorial origin of this disorder to offer possible preventive and therapeutic interventions. With heritability accounting for 75% to 80% of the variability seen in ADHD, the remaining are explained through environmental risk factors that are exposed during critical period of pre-, peri-, and postnatal development. Though literature on the risk factors have been mostly controversial, certain associations have been made with regards to ADHD pathophysiology.

scholarly journals Emotional impulsivity and deficient emotional self-regulation might be core symptoms of ADHD

2019 ◽  
Keyword(s):  
Quality Of Life ◽  
Attention Deficit Hyperactivity Disorder ◽  
Social Adjustment ◽  
Self Regulation ◽  
Poor Quality ◽  
Emotional Symptoms ◽  
Hyperactivity Disorder ◽  
Emotional Impulsivity ◽  
Core Symptoms

A large proportion of children with attention-deficit/hyperactivity disorder (ADHD) exhibit notable emotion-related problems (or “emotional symptoms”). These emotional symptoms seem to associate with poor quality of life, impaired social adjustment and reduced marital status.

scholarly journals Keratin 19 interacts with GSK3β to regulate its nuclear accumulation and degradation of cyclin D3

2021 ◽  
Author(s):  
Pooja Sharma ◽  
Sarah Tiufekchiev ◽  
Victoria Lising ◽  
Seung Woo Chung ◽  
Jung Soo Suk ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cyclin D3 ◽  
Nuclear Accumulation ◽  
Cyclin Dependent Kinase ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Keratin 19 ◽  
Head Domain ◽  
Cancer Types ◽  
Potential Strategy

Cyclin D3 regulates the G1/S transition and is frequently overexpressed in several cancer types including breast cancer, where it promotes tumor progression. Here, we show that a cytoskeletal protein keratin 19 (K19) physically interacts with a serine/threonine kinase GSK3β and prevents GSK3β-dependent degradation of cyclin D3. The absence of K19 allowed active GSK3β to accumulate in the nucleus and degrade cyclin D3. Specifically, the head domain of K19 was required to sustain inhibitory phosphorylation of GSK3β Ser9, prevent nuclear accumulation of GSK3β, and maintain cyclin D3 levels and cell proliferation. K19 was found to interact with GSK3β and K19-GSK3β interaction was mapped out to require Ser10 and Ser35 residues on the head domain of K19. Unlike wildtype K19, S10A and S35A mutants failed to maintain total and nuclear cyclin D3 levels and induce cell proliferation. Finally, we show that the K19-GSK3β-cyclin D3 pathway affected sensitivity of cells towards inhibitors to cyclin dependent kinase 4 and 6 (CDK4/6). Overall, these findings establish a role for K19 in the regulation of GSK3β-cyclin D3 pathway and demonstrate a potential strategy for overcoming resistance to CDK4/6 inhibitors.

Sign in / Sign up

Export Citation Format

Share Document