Longitudinal Course of Bipolar Disorder in Youth With High-Functioning Autism Spectrum Disorder.

OBJECTIVE: To provide the first longitudinal characterization of mood and psychosocial functioning in youth with comorbid bipolar (BD) and autism spectrum (ASD) disorders. METHOD: The Course and Outcome of Bipolar Youth study followed 368 youth (aged 7-17 years) with DSM-IV bipolar I (BP-I), BP-II, or Not Otherwise Specified (NOS) for, on average, 9 years using the Longitudinal Interval Follow-up Evaluation. This subgroup analysis compared youth with and without ASD on clinical presentation, percentage of time with mood symptomatology, and psychosocial functioning. RESULTS: Thirty youth (∼8%) met DSM-IV criteria for Asperger's disorder or pervasive developmental disorder-NOS (referred to here as ASD). Lifetime worst episode severity was similar in both groups, but youth with both BD and ASD (BD+ASD) had elevated rates of comorbid attention-deficit/hyperactivity and obsessive-compulsive disorders, were younger at intake, and had an earlier onset of mood symptoms. Over time, in both groups, the proportion of predominantly euthymic youth increased, and episode recurrence decreased. Compared to youth with BD, the clinical presentation of youth with BD+ASD more frequently involved distractibility, racing thoughts, depressed mood, social withdrawal, and low reactivity of negative mood states. ASD-related symptomatic differences were generally strongest early and decreased over time. Youth with BD+ASD had significantly greater impairment in friendships throughout follow-up. CONCLUSION: Youth with BD+ASD exhibit typical BD mood symptoms but with earlier onset, mixed symptom presentation, and additive functional impairments. Significant amelioration of clinical symptoms occurred over time, suggesting that early recognition and treatment of mood disorders in youth with ASD may improve clinical outcomes.

Emotion regulation patterns in adolescents with high-functioning autism spectrum disorder: comparison to typically developing adolescents and association with psychiatric symptoms.

Autism spectrum disorder (ASD) is often associated with poor emotional control and psychopathology, such as anxiety and depression; however, little is known about the underlying mechanisms. Emotion regulation (ER) is a potential contributing factor, but there has been limited research on ER and its role in comorbid psychopathology in ASD. In this study, we compared self-reported ER with self- and parent reports of psychopathology in 25 high-functioning adolescents with ASD and 23 age- and Intelligence Quotient (IQ)-matched typically developing controls. Contrary to expectations, both groups reported similar levels of adaptive, voluntary forms of ER (problem solving, acceptance, etc.). However, the ASD group reported significantly greater use of involuntary forms of ER that are typically maladaptive, including remaining focused on the stressor (e.g. rumination and emotional arousal) and shutting down (e.g. emotional numbing and being unable to think or act). Associations between ER and psychopathology were generally more robust using self-report rather than parent report. For both groups, greater endorsement of involuntary ER strategies was associated with higher ratings of psychopathology, whereas voluntary ER strategies focused on changing or adapting to the situation were significantly associated with lower levels of psychopathology. The magnitude and direction of association between ER types and psychopathology were similar for measures of depression and anxiety. These findings can help guide the development of psychosocial treatments targeting dysfunctional ER in adolescents with ASD. Interventions focused on ER as a transdiagnostic process may be a more robust method to improve emotional control and decrease emotional distress in ASD than disorder-specific interventions.

Both synthesis and reuptake are critical for replenishing the releasable serotonin pool in Drosophila.

The two main sources of serotonin available for release are expected to be newly synthesized serotonin and serotonin recycled after reuptake by the serotonin transporter. However, their relative importance for maintaining release and the time course of regulation are unknown. We studied serotonin signaling in the ventral nerve cord of the larval Drosophila CNS. Fast-scan cyclic voltammetry at implanted microelectrodes was used to detect serotonin elicited by channelrhodopsin2-mediated depolarization. The effects of reuptake were probed by incubating in cocaine, which is selective for the serotonin transporter in Drosophila. p-chlorophenylalanine, an inhibitor of tryptophan hydroxylase2, was used to investigate the effects of synthesis. Stimulations were repeated at various intervals to assess the time course of recovery of the releasable pool. Reuptake is important for the rapid replenishment of the releasable pool, on the 1 min time scale. Synthesis is critical to the longer-term replenishment (10 min) of the releasable pool, especially when reuptake is also inhibited. Concurrent synthesis and reuptake inhibition decreased both serotonin tissue content measured by immunohistochemistry (by 50%) and the initial amount of evoked serotonin (by 65%). Decreases in evoked serotonin are rescued by inhibiting action potential propagation with tetrodotoxin, implicating endogenous activity in the depletion. These results show synthesis is necessary to replenish part of the releasable serotonin pool that is depleted after reuptake inhibition, suggesting that regulation of synthesis may modulate the effects of serotonin reuptake inhibitors.

Quantitative evaluation of serotonin release and clearance in Drosophila.

Serotonin signaling plays a key role in the regulation of development, mood and behavior. Drosophila is well suited for the study of the basic mechanisms of serotonergic signaling, but the small size of its nervous system has previously precluded the direct measurements of neurotransmitters. This study demonstrates the first real-time measurements of changes in extracellular monoamine concentrations in a single larval Drosophila ventral nerve cord. Channelrhodopsin-2-mediated, neuronal type-specific stimulation is used to elicit endogenous serotonin release, which is detected using fast-scan cyclic voltammetry at an implanted microelectrode. Release is decreased when serotonin synthesis or packaging are pharmacologically inhibited, confirming that the detected substance is serotonin. Similar to tetanus-evoked serotonin release in mammals, evoked serotonin concentrations are 280-640nM in the fly, depending on the stimulation length. Extracellular serotonin signaling is prolonged after administering cocaine or fluoxetine, showing that transport regulates the clearance of serotonin from the extracellular space. When ChR2 is targeted to dopaminergic neurons, dopamine release is measured demonstrating that this method is broadly applicable to other neurotransmitter systems. This study shows that the dynamics of serotonin release and reuptake in Drosophila are analogous to those in mammals, making this simple organism more useful for the study of the basic physiological mechanisms of serotonergic signaling.

Developmental effects of SSRIs: lessons learned from animal studies.

Selective serotonin reuptake inhibitors (SSRIs) are utilized in the treatment of depression in pregnant and lactating women. SSRIs may be passed to the fetus through the placenta and the neonate through breastfeeding, potentially exposing them to SSRIs during peri- and postnatal development. However, the long-term effects of this SSRI exposure are still largely unknown. The simplicity and genetic amenability of model organisms provides a critical experimental advantage compared to studies with humans. This review will assess the current research done in animals that sheds light on the role of serotonin during development and the possible effects of SSRIs. Experimental studies in rodents show that administration of SSRIs during a key developmental window creates changes in brain circuitry and maladaptive behaviors that persist into adulthood. Similar changes result from the inhibition of the serotonin transporter or monoamine oxidase, implicating these two regulators of serotonin signaling in developmental changes. Understanding the role of serotonin in brain development is critical to identifying the possible effects of SSRI exposure.

Bone marrow-derived cells contribute to epithelial engraftment during wound healing.

Recent findings suggest that bone marrow-derived cells (BMDC) may contribute to tissue maintenance throughout the body. However, it is not yet known whether marrow-derived epithelial cells are capable of undergoing proliferation. Our laboratory has shown that BMDC engraft as keratinocytes in the skin at low levels (

Normal and aberrant craniofacial myogenesis by grafted trunk somitic and segmental plate mesoderm.

Our research assesses the ability of three trunk mesodermal populations -- medial and lateral halves of newly formed somites, and presomitic (segmental plate) mesenchyme -- to participate in the differentiation and morphogenesis of craniofacial muscles. Grafts from quail donor embryos were placed in mesodermal pockets adjacent to the midbrain-hindbrain boundary, prior to the onset of neural crest migration, in chick host embryos. This encompasses the site where the lateral rectus and the proximal first branchial arch muscle primordia arise. The distribution and differentiation of graft-derived cells were assayed using QCPN and QH1 antibodies to identify all quail cells and quail endothelial cells, respectively. Chimeric embryos were assayed for expression of myf5, myod, paraxis and lbx1, and the synthesis of myosin heavy chain (MyHC), between 1 and 6 days later (stages 14-30). Heterotopic and control (orthotopic) transplants consistently produced invasive angioblasts, and contributed to the lateral rectus and proximal first branchial arch muscles; many also contributed to the dorsal oblique muscle. The spatiotemporal patterns of transcription factor and MyHC expression by these trunk cells mimicked those of normal head muscles. Heterotopic grafts also gave rise to many ectopic muscles. These were observed in somite-like condensations at the implant site, in dense mesenchymal aggregates adjacent to the midbrain-hindbrain boundary, and in numerous small condensations scattered deep to the dorsal margin of the eye. Cells in ectopic condensations expressed trunk transcription factors and differentiated rapidly, mimicking the trunk myogenic timetable. A novel discovery was the formation by grafted trunk mesoderm of many mononucleated myocytes and irregularly oriented myotubes deep to the eye. These results establish that the head environment is able to support the progressive differentiation of several distinct trunk myogenic progenitor populations, over-riding whatever biases were present at the time of grafting. The spatial and temporal control of head muscle differentiation and morphogenesis are very site specific, and head mesoderm outside of these sites is normally refractory to, or inhibited by, the signals that initiate ectopic myogenesis by grafted trunk mesoderm cells.

Genetics analysis of mouse mutations Abnormal feet and tail and rough coat, which cause developmental abnormalities and alopecia.

Mutations in the mouse Brachyury (T) gene are characterized by a dominant reduction of tail length and recessive lethality. Two quantitative trait loci, Brachyury-modifier 1 and 2 (Brm1 and Brm2) are defined by alleles that enhance the short-tail Brachyury phenotype. Here we report on a genetic analysis of a visible dominant mutation Abnormal feet and tail (Aft) located in the vicinity of Brm1. Affected animals display kinky tails and syndactyly in the hindlimbs, both likely resulting from a defect in apoptosis. We observed an unusual genetic incompatibility between Aft and certain genetic backgrounds. We show that Aft and T are likely to interact genetically, since some double heterozygotes are tailless. In addition to the tail and hindlimb phenotypes, Aft-bearing mutants display characteristic late-onset skin lesions. We therefore tested for allelism between Aft and a closely linked recessive mutation rough coat (rc) and found that these two mutations are likely nonallelic. Our results provide a valuable resource for the study of mammalian skin development and contribute to the genetic analysis of Brachyury function.