VGLUT2 Trafficking Is Differentially Regulated by Adaptor Proteins AP-1 and AP-3.

Release of the major excitatory neurotransmitter glutamate by synaptic vesicle exocytosis depends on glutamate loading into synaptic vesicles by vesicular glutamate transporters (VGLUTs). The two principal isoforms, VGLUT1 and 2, exhibit a complementary pattern of expression in adult brain that broadly distinguishes cortical (VGLUT1) and subcortical (VGLUT2) systems, and correlates with distinct physiological properties in synapses expressing these isoforms. Differential trafficking of VGLUT1 and 2 has been suggested to underlie their functional diversity. Increasing evidence suggests individual synaptic vesicle proteins use specific sorting signals to engage specialized biochemical mechanisms to regulate their recycling. We observed that VGLUT2 recycles differently in response to high frequency stimulation than VGLUT1. Here we further explore the trafficking of VGLUT2 using a pHluorin-based reporter, VGLUT2-pH. VGLUT2-pH exhibits slower rates of both exocytosis and endocytosis than VGLUT1-pH. VGLUT2-pH recycling is slower than VGLUT1-pH in both hippocampal neurons, which endogenously express mostly VGLUT1, and thalamic neurons, which endogenously express mostly VGLUT2, indicating that protein identity, not synaptic vesicle membrane or neuronal cell type, controls sorting. We characterize sorting signals in the C-terminal dileucine-like motif, which plays a crucial role in VGLUT2 trafficking. Disruption of this motif abolishes synaptic targeting of VGLUT2 and essentially eliminates endocytosis of the transporter. Mutational and biochemical analysis demonstrates that clathrin adaptor proteins (APs) interact with VGLUT2 at the dileucine-like motif. VGLUT2 interacts with AP-2, a well-studied adaptor protein for clathrin mediated endocytosis. In addition, VGLUT2 also interacts with the alternate adaptors, AP-1 and AP-3. VGLUT2 relies on distinct recycling mechanisms from VGLUT1. Abrogation of these differences by pharmacological and molecular inhibition reveals that these mechanisms are dependent on the adaptor proteins AP-1 and AP-3. Further, shRNA-mediated knockdown reveals differential roles for AP-1 and AP-3 in VGLUT2 recycling.

Management of auditory hallucinations as a sequela of traumatic brain injury: a case report and a relevant literature review.

A patient with progressively worsening auditory hallucinations and 30-year history of traumatic brain injury (TBI) was reported. To formulate a comprehensive diagnostic and treatment approach to patients with auditory sensory disturbances and other neuropsychiatric sequela of a TBI, an electronic search of the major behavioral science databases (PubMed, PsycINFO, Medline) and a textbook review were conducted to retrieve studies detailing the clinical characteristics, biological mechanisms, and therapeutic approaches to post-TBI psychosis. Additional references were incorporated from the bibliographies of the retrieved articles. Although infrequent, auditory hallucinations is a debilitating complication of TBI that can manifest itself 4-5 years after the occurrence of TBI. Because the age range of TBI survivors is 15-24 years, and the chance of developing post-TBI psychosis is reported to be up to 20%, this chronic neuropsychiatric complication and the available treatment options warrant close scrutiny from the clinical and the biomedical research community. Our case report and literature review demonstrates a clear need for a large, well-designed randomized trials to compare properties and efficacies of different, available, and promising pharmacotherapy agents for the treatment of post-TBI psychosis.

Ecstasy use and serotonin syndrome: a neglected danger to adolescents and young adults prescribed selective serotonin reuptake inhibitors.

BACKGROUND: At present, there are scarce clinical and basic lab data concerning the risk of acute serotonin toxicity from selective serotonin reuptake inhibitors (SSRIs) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) co-administration. The health care community can strongly benefit from efforts to address the high risks associated with serotonin syndrome from this specific drug combination. OBJECTIVE: The aim of this work is to review the risk of serotonin syndrome in adolescents and young adults prescribed with SSRIs and are concurrently using ecstasy. DATA SOURCES: An electronic search of the major behavioral science bibliographic databases (Pubmed, PsycINFO, Medline) was conducted to retrieve peer-reviewed articles, which detail the clinical characteristics, biological mechanisms and social implications of SSRIs, MDMA, and their potential synergism in causing serotonin syndrome in the pediatric and young adult population. Search terms included "serotonin syndrome", "ecstasy", "MDMA", "pediatric", and "SSRI". Additional references were incorporated from the bibliographies of these retrieved articles. RESULTS: MDMA, in combination with the widely-prescribed SSRI antidepressant class, can lead to rapid, synergistic rise of serotonin (5-HT) concentration in the central nervous system, leading to the acute medical emergency known as serotonin syndrome. This review addresses such complication through an exploration of the theoretical mechanisms and clinical manifestations of this life-threatening pharmacological interaction. CONCLUSION: The increasing incidences of recreational ecstasy use and SSRI pharmacotherapy among multiple psychiatric disorders in the adolescent population have made this an overlooked yet increasingly relevant danger, which poses a threat to public health. This can be curbed through further research, as well as greater health care provision and attention from a regulatory body owing.

Bullying, psychiatric pathology and suicidal behavior.

Bullying is a highly prevalent behavior which carries a significant social, medical and financial cost for its victims and perpetrators, with powerful and long-lasting psychological and social impact. Bullying has been defined as a specific form of intentional, repeated aggression, that involves a disparity of power between the victim(s) and perpetrator(s). The aggression can take physical, verbal or gestural forms. The behavior of bullying crosses sociodemographic categories of age, gender, ethnicity, level of academic achievement and professional environment. It has been abundantly observed by teachers and parents in elementary schools, but has also shown its negative presence in corporate boardrooms. The direct outcome of bullying, for both victims and perpetrators, is an increased risk of psychiatric disorders including depression, post-traumatic stress disorder, anxiety disorders, substance abuse and suicidal behavior. Cruelty (and bullying, as one of its manifestations) breaks the basis of morality. Mental health professionals usually treat the victims of those actions unfortunately long after they have been exposed to the harm. The evidence does not support the idea that the majority of cruel actions are intrinsically "pathological", in the sense of being motivated by "mental disorders". Therefore, only moral rules and legal actions - but not psychiatric or psychological interventions - may dissuade humans from this form of cruelty.

The underexamined association between posttraumatic stress disorder, medical illness and suicidal behavior.

Posttraumatic stress disorder (PTSD) is concerning not only because of the severity and chronicity of its symptoms - including distressing nightmares, flashbacks, anxiety attacks and maladaptive patterns of avoidant and nearly paranoid behavior - but also because of the wide spectrum of clinical and social impairments it is tightly associated with. The most striking example of clinical morbidity associated with PTSD is the well-known increase in the risk of suicidal behavior. Given that PTSD and medical illnesses increase the likelihood of suicide separately and independently, it is reasonable to suggest that the risk of suicidal behavior differs between patients suffering from PTSD comorbid with medical illnesses and patients having either condition alone. The available data point toward a novel clinical notion, an altered risk of suicidal behavior in patients suffering from comorbid PTSD and medical illnesses. This area of overlap between medicine and psychiatry is still in its infancy, with many unanswered questions about the rate, patterns and psychobiological mechanisms of suicidal behavior in this patient population. The positive association between PTSD, medical illness and suicidal behavior that appears to exist in the adult population, most likely affects the pediatric population as well. Closer investigation into the significance of the association between chronic medical illnesses, PTSD and suicidality in children, adolescents and adults is necessary.

Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency.

BACKGROUND: 22q13 deletion syndrome, also known as Phelan-McDermid syndrome, is a neurodevelopmental disorder characterized by intellectual disability, hypotonia, delayed or absent speech, and autistic features. SHANK3 has been identified as the critical gene in the neurological and behavioral aspects of this syndrome. The phenotype of SHANK3 deficiency has been described primarily from case studies, with limited evaluation of behavioral and cognitive deficits. The present study used a prospective design and inter-disciplinary clinical evaluations to assess patients with SHANK3 deficiency, with the goal of providing a comprehensive picture of the medical and behavioral profile of the syndrome. METHODS: A serially ascertained sample of patients with SHANK3 deficiency (n = 32) was evaluated by a team of child psychiatrists, neurologists, clinical geneticists, molecular geneticists and psychologists. Patients were evaluated for autism spectrum disorder using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule-G. RESULTS: Thirty participants with 22q13.3 deletions ranging in size from 101 kb to 8.45 Mb and two participants with de novo SHANK3 mutations were included. The sample was characterized by high rates of autism spectrum disorder: 27 (84%) met criteria for autism spectrum disorder and 24 (75%) for autistic disorder. Most patients (77%) exhibited severe to profound intellectual disability and only five (19%) used some words spontaneously to communicate. Dysmorphic features, hypotonia, gait disturbance, recurring upper respiratory tract infections, gastroesophageal reflux and seizures were also common. Analysis of genotype-phenotype correlations indicated that larger deletions were associated with increased levels of dysmorphic features, medical comorbidities and social communication impairments related to autism. Analyses of individuals with small deletions or point mutations identified features related to SHANK3 haploinsufficiency, including ASD, seizures and abnormal EEG, hypotonia, sleep disturbances, abnormal brain MRI, gastroesophageal reflux, and certain dysmorphic features. CONCLUSIONS: This study supports findings from previous research on the severity of intellectual, motor, and speech impairments seen in SHANK3 deficiency, and highlights the prominence of autism spectrum disorder in the syndrome. Limitations of existing evaluation tools are discussed, along with the need for natural history studies to inform clinical monitoring and treatment development in SHANK3 deficiency.

Cognitive effects of quetiapine in a patient with dementia with Lewy bodies.

A recent large-scale randomized controlled clinical trial, the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease study, found a significant worsening of cognitive functioning in a sample of patients with Alzheimer's disease. To date there have been no equally powered studies examining the cognitive effects of atypical antipsychotics in patients with dementia with Lewy bodies, the second most prevalent neurodegenerative disorder. This case report describes a significant cognitive improvement observed through the use of an atypical antipsychotic in a patient with dementia with Lewy bodies. The observed divergence in cognitive responsiveness is discussed mechanistically on both the clinical and neuromolecular level. Limitations to this case study design are presented and discussed. The prudence of caution in importing the results of the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease study to the dementia with Lewy bodies population is summarized and presented for psychiatrists, neurologists and primary care providers, with an intent to stimulate discussion and further research.

The importance of patient-provider communication in end-of-life care.

Successful formulation and implementation of end-of-life care requires ongoing communication with the patient. When patients, for reasons of general medical or psychiatric illness, fail to verbally communicate, providers must be receptive to messages conveyed through alternate avenues of communication. We present the narrative of a man with schizophrenia who wished to forgo hemodialysis as a study in the ethical importance of attention to nonverbal communication. A multilayered understanding of the patient, as may be provided by both behavioral and motivational models, can inform the provider's ability to receive, process, and represent communicated content to the patient or his or her surrogate decision-maker.