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1.
Fly (Austin) ; 7(4): 267-79, 2013.
Article in English | MEDLINE | ID: mdl-24091420

ABSTRACT

Infantile-onset neuronal ceroid lipofuscinosis (INCL) is a severe pediatric neurodegenerative disorder produced by mutations in the gene encoding palmitoyl-protein thioesterase 1 (Ppt1). This enzyme is responsible for the removal of a palmitate group from its substrate proteins, which may include presynaptic proteins like SNAP-25, cysteine string protein (CSP), dynamin, and synaptotagmin. The fruit fly, Drosophila melanogaster, has been a powerful model system for studying the functions of these proteins and the molecular basis of neurological disorders like the NCLs. Genetic modifier screens and tracer uptake studies in Ppt1 mutant larval garland cells have suggested that Ppt1 plays a role in endocytic trafficking. We have extended this analysis to examine the involvement of Ppt1 in synaptic function at the Drosophila larval neuromuscular junction (NMJ). Mutations in Ppt1 genetically interact with temperature sensitive mutations in the Drosophila dynamin gene shibire, accelerating the paralytic behavior of shibire mutants at 27 °C. Electrophysiological work in NMJs of Ppt1-deficient larvae has revealed an increase in miniature excitatory junctional potentials (EJPs) and a significant depression of evoked EJPs in response to repetitive (10 hz) stimulation. Endocytosis was further examined in Ppt1-mutant larvae using FM1-43 uptake assays, demonstrating a significant decrease in FM1-43 uptake at the mutant NMJs. Finally, Ppt1-deficient and Ppt1 point mutant larvae display defects in locomotion that are consistent with alterations in synaptic function. Taken together, our genetic, cellular, and electrophysiological analyses suggest a direct role for Ppt1 in synaptic vesicle exo- and endocytosis at motor nerve terminals of the Drosophila NMJ.


Subject(s)
Drosophila Proteins/genetics , Drosophila melanogaster/genetics , Endocytosis/genetics , Exocytosis/genetics , Membrane Proteins/genetics , Animals , Drosophila Proteins/metabolism , Drosophila Proteins/physiology , Drosophila melanogaster/cytology , Drosophila melanogaster/physiology , Larva/cytology , Larva/genetics , Larva/metabolism , Locomotion/genetics , Membrane Proteins/metabolism , Membrane Proteins/physiology , Mutation , Neuromuscular Junction/growth & development , Neuromuscular Junction/metabolism , Synapses/metabolism , Synapses/physiology , Thiolester Hydrolases
2.
J Psychiatry Neurosci ; 38(6): 407-16, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23906351

ABSTRACT

BACKGROUND: Children with bipolar disorder (BD) or severe mood dysregulation (SMD) show behavioural and neural deficits during facial emotion processing. In those with other psychiatric disorders, such deficits have been associated with reduced attention to eye regions while looking at faces. METHODS: We examined gaze fixation patterns during a facial emotion labelling task among children with pediatric BD and SMD and among healthy controls. Participants viewed facial expressions with varying emotions (anger, fear, sadness, happiness, neutral) and emotional levels (60%, 80%, 100%) and labelled emotional expressions. RESULTS: Our study included 22 children with BD, 28 with SMD and 22 controls. Across all facial emotions, children with BD and SMD made more labelling errors than controls. Compared with controls, children with BD spent less time looking at eyes and made fewer eye fixations across emotional expressions. Gaze patterns in children with SMD tended to fall between those of children with BD and controls, although they did not differ significantly from either of these groups on most measures. Decreased fixations to eyes correlated with lower labelling accuracy in children with BD, but not in those with SMD or in controls. LIMITATIONS: Most children with BD were medicated, which precluded our ability to evaluate medication effects on gaze patterns. CONCLUSION: Facial emotion labelling deficits in children with BD are associated with impaired attention to eyes. Future research should examine whether impaired attention to eyes is associated with neural dysfunction. Eye gaze deficits in children with BD during facial emotion labelling may also have treatment implications. Finally, children with SMD exhibited decreased attention to eyes to a lesser extent than those with BD, and these equivocal findings are worthy of further study.


Subject(s)
Bipolar Disorder/physiopathology , Facial Expression , Fixation, Ocular/physiology , Mood Disorders/physiopathology , Adolescent , Case-Control Studies , Child , Female , Humans , Male , Photic Stimulation , Social Perception
3.
Prog Neuropsychopharmacol Biol Psychiatry ; 38(2): 127-33, 2012 Aug 07.
Article in English | MEDLINE | ID: mdl-22414616

ABSTRACT

BACKGROUND: A better understanding of the neural underpinnings of bipolar disorder (BD) can be obtained by examining brain activity in symptom-free individuals at risk for BD. This study examined the neural correlates of motor inhibition in a sample of symptom-free youths at familial risk for BD. METHODS: 19 euthymic youths with BD, 13 asymptomatic youths with a first-degree relative with BD, and 21 healthy comparison children completed the stop signal task in a 3 T scanner. RESULTS: Children at familial risk for BD exhibited increased putamen activation during unsuccessful inhibition that distinguished them from both healthy and BD children. Youths with BD exhibited reduced activation of the right nucleus accumbens during unsuccessful inhibition as compared to the other participant groups. CONCLUSIONS: Striatal activation patterns differ between youths at risk for BD and healthy comparison children during a motor inhibition task.


Subject(s)
Bipolar Disorder/physiopathology , Corpus Striatum/physiopathology , Inhibition, Psychological , Psychomotor Performance/physiology , Adolescent , Attention/physiology , Brain Mapping , Child , Female , Humans , Magnetic Resonance Imaging , Male , Neuropsychological Tests , Reaction Time/physiology , Risk
4.
Biol Psychol ; 89(1): 148-55, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22008364

ABSTRACT

Controversy exists about whether non-episodic irritability (operationalized as severe mood dysregulation, SMD) should be considered a developmental presentation of pediatric bipolar disorder (BD). While assessments of brain function may address this controversy, only one fMRI study has compared BD versus SMD. We compared neural activation in BD, SMD, and controls during a motor inhibition task, since motor disinhibition is an important clinical feature in both BD and SMD. During failed inhibition, BD youths exhibited less activation in the right anterior cingulate cortex (ACC) and right nucleus accumbens relative to both SMD and healthy youths. Exploratory analyses indicate that, in BD youths, reduced activation in the right ACC may be independent of comorbid ADHD. These findings highlight neural distinctions between the phenotypically related BD and SMD populations.


Subject(s)
Bipolar Disorder/pathology , Bipolar Disorder/psychology , Gyrus Cinguli/physiopathology , Inhibition, Psychological , Irritable Mood/physiology , Motor Activity/physiology , Adolescent , Analysis of Variance , Attention Deficit Disorder with Hyperactivity/physiopathology , Brain Mapping , Child , Female , Humans , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Male , Mood Disorders , Neuropsychological Tests , Psychiatric Status Rating Scales , Signal Detection, Psychological/physiology
5.
J Psychiatr Res ; 46(1): 22-30, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22024484

ABSTRACT

BACKGROUND: Youth with bipolar disorder (BD) show behavioral and neural deficits in cognitive flexibility; however, whether such deficits exist among youths at risk for BD has not been explored. METHODS: The current fMRI study examined the neural basis of cognitive flexibility in BD youth (n = 28), unaffected youth at risk for BD (AR; n = 13), and healthy volunteer youth (HV; n = 21) by comparing brain activation patterns while participants performed the change task. On change trials, subjects must inhibit a prepotent response and execute an alternate one. RESULTS: During successful change trials, both BD and AR youth had increased right ventrolateral prefrontal and inferior parietal activity, compared to HV youth. During failed change trials, both BD and AR youth exhibited increased caudate activation relative to HV youth, but BD youth showed increased activation in the subgenual anterior cingulate cortex (ACC) relative to the other two groups. CONCLUSIONS: Abnormal activity in ventrolateral prefrontal cortex, inferior parietal cortex, and striatum during a cognitive flexibility task may represent a potential BD endophenotype, but subgenual ACC dysfunction may represent a marker of BD illness itself.


Subject(s)
Bipolar Disorder/complications , Brain Mapping , Brain/pathology , Cognition Disorders/etiology , Cognition Disorders/pathology , Adolescent , Analysis of Variance , Attention , Bipolar Disorder/genetics , Brain/blood supply , Child , Female , Humans , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Male , Neuropsychological Tests , Oxygen/blood , Psychiatric Status Rating Scales , Reaction Time
6.
Dev Sci ; 14(1): 148-61, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21159096

ABSTRACT

This neuroimaging study examines the development of cognitive flexibility using the Change task in a sample of youths and adults. The Change task requires subjects to inhibit a prepotent response and substitute an alternative response, and the task incorporates an algorithm that adjusts task difficulty in response to subject performance. Data from both groups combined show a network of prefrontal and parietal areas that are active during the task. For adults vs. youths, a distributed network was more active for successful change trials versus go, baseline, or unsuccessful change trials. This network included areas involved in rule representation, retrieval (lateral PFC), and switching (medial PFC and parietal regions). These results are consistent with data from previous task-switching experiments and inform developmental understandings of cognitive flexibility.


Subject(s)
Cognition/physiology , Parietal Lobe/physiology , Prefrontal Cortex/physiology , Psychomotor Performance , Adolescent , Adult , Behavior , Brain Mapping , Child , Executive Function , Female , Humans , Magnetic Resonance Imaging , Male , Task Performance and Analysis
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