- Email: [email protected]
337. Neuropsychiatric Profiles of Children and Adolescents with Hypothalamic Hamartomas
Biological Psychiatry
Thursday Abstracts
Supported By: NIH R01-MH10028 Keywords: Autism Spectrum Disorder, Tractography, Gender differences
White
Matter
336. VIP Interneuron Cholinergic Responses are Altered in Multiple Models of Autism Margaret Cunniff and Vikaas Sohal University of California, San Francisco Background: VIP interneurons are known to be recruited by behaviorally alert states and rewarding or aversive stimuli. VIP interneurons are also targets of the neuromodulator acetylcholine. However, the exact relationship of VIP interneurons to behavior, and possible alterations in VIP interneurons associated with disorders such as autism remain largely unknown. Methods: We used patch clamp recording in brain slices to characterize the electrophysiological properties of VIP interneurons in the prefrontal cortex of wildtype mice and two distinct models of autism, Fragile-X knockout mice and prenatal valproate exposure. We also characterized the responses of VIP interneurons to the cholinergic agonist carbachol. VIP interneurons were bilaterally optogentically inhibited in the mPFC during social behavior. VIP interneuron activity during social behavior was recorded using fiber photometry and calcium imaging. Statistics were done with ANOVAs. Results: In wildtype mice, acetylcholine causes a significant increase in spike halfwidth and excitability in VIP interneurons. In both autism models, however, this increase in excitability is impaired and the increase in halfwidth is enhanced. Inhibiting VIP interneurons optogenetically during social behavior causes an increase in social interaction in wildtype mice. Recording the bulk calcium signal from VIP interneurons using fiber photometry shows VIP interneurons decrease their activity following the initiation of social interaction. Conclusions: VIP interneurons are robustly modulated by acetylcholine, and this modulation is consistently altered in two distinct mouse models of autism. Furthermore, VIP interneurons play a major role in modulating social interaction. VIP interneurons thus may contribute to abnormal social behavior in autism and represent a novel therapeutic target. Supported By: SFARI, NSF Keywords: acetylcholine, Autism, interneurons, social behavior, optogenetics
337. Neuropsychiatric Profiles of Children and Adolescents with Hypothalamic Hamartomas Georgina Corbet Burcher1, Elisabetta Caredda2, Robert Wilkinson2, Sophie Bennett2, Helen Cross3, Martin Tisdall2, Helen Spoudeas2, Sue Harrison2, Sophia Varadkar2, and Isobel Heyman3 Imperial College London, 2Great Ormond Street Hospital, London, 3University College London 1
Background: Hypothalamic hamartomas are rare brain malformations characterised by a clinical syndrome of
S138
seizures, central precocious puberty, behavioral, emotional and cognitive difficulties. Psychiatric symptoms often present the greatest burden of morbidity for patients and families. Due to the rarity of the disease, the heterogeneity of the presentation, and the multifactorial aetiology, prognosis is varied and management strategies are yet to be standardised. Methods: The notes of 46 pediatric cases with hypothalamic hamartomas were examined retrospectively. Demographics, psychiatric symptoms, cognitive functioning, epileptic profiles, and pubertal status were recorded. ICD-10 codes for psychiatric disorder were assigned to applicable cases. Results: 61% of cases were male. The mean age at diagnosis was 4.2 years (0-14 years). 71.7% of the cases met criteria for $ 1 ICD-10 Axis 1 psychiatric disorder. Attention Deficit Hyperactivity Disorder, Generalized Anxiety Disorder and Autism Spectrum Disorder were most frequent. 46% experienced characteristic rage attacks. 50% had some degree of intellectual disability, most commonly mild. 63% of cases experienced seizures, most commonly gelastic in nature. 40% of cases had precocious puberty. Conclusions: This data set represents one of the largest in the pediatric hypothalamic hamartoma literature. A significant proportion of cases have psychiatric disorders and intellectual disability. These presenting features are a product of numerous aetiological factors. The direct brain-behaviour effects from disrupted hypothalamic functioning, possible epileptic encephalopathy resulting from refractory seizures and impact of antiepileptic medications are all contributory. These findings also provide insight into the pathoaetiology of other neuropsychiatric disorders where hypothalamic dysfunction has been implicated. Keywords: hypothalamic hamartoma, seizures, aggression
338. Enabling Precision Psychiatry through ‘omics’: From Biomarkers to Biological Pathways Brisa Fernandes1 and Michael Berk2 1 Deakin University, School of Medicine, 2Deakin University, IMPACT Strategic Research Centre, School of Medicine, Faculty of Health, Geelong
Background: Schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) are severe mental disorders regarded as syndromes and defined by a clustering spectrum of signs and symptoms. Thus far, there is no single defining clinical or pathological hallmark for any of those disorders, and their symptoms profiles overlap with each other in what is considered the schizoaffective spectrum. The lack of knowledge about their neurobiology hampers the identification of biomarkers, which could guide risk, prognosis, clinical diagnosis and therapeutic decisions. Methods: We performed a systematic review of all studies employing proteomics or metabolomics in peripheral blood of persons with SZ, BD, or MDD compared to controls and extracted all differentially expressed proteins. After, we derived the involved biological pathways according to which altered proteins were unique to SZ, BD, or MDD and to which were shared using Ingenuity Software.
Biological Psychiatry May 15, 2017; 81:S1–S139 www.sobp.org/journal
Thursday Abstracts
Supported By: NIH R01-MH10028 Keywords: Autism Spectrum Disorder, Tractography, Gender differences
White
Matter
336. VIP Interneuron Cholinergic Responses are Altered in Multiple Models of Autism Margaret Cunniff and Vikaas Sohal University of California, San Francisco Background: VIP interneurons are known to be recruited by behaviorally alert states and rewarding or aversive stimuli. VIP interneurons are also targets of the neuromodulator acetylcholine. However, the exact relationship of VIP interneurons to behavior, and possible alterations in VIP interneurons associated with disorders such as autism remain largely unknown. Methods: We used patch clamp recording in brain slices to characterize the electrophysiological properties of VIP interneurons in the prefrontal cortex of wildtype mice and two distinct models of autism, Fragile-X knockout mice and prenatal valproate exposure. We also characterized the responses of VIP interneurons to the cholinergic agonist carbachol. VIP interneurons were bilaterally optogentically inhibited in the mPFC during social behavior. VIP interneuron activity during social behavior was recorded using fiber photometry and calcium imaging. Statistics were done with ANOVAs. Results: In wildtype mice, acetylcholine causes a significant increase in spike halfwidth and excitability in VIP interneurons. In both autism models, however, this increase in excitability is impaired and the increase in halfwidth is enhanced. Inhibiting VIP interneurons optogenetically during social behavior causes an increase in social interaction in wildtype mice. Recording the bulk calcium signal from VIP interneurons using fiber photometry shows VIP interneurons decrease their activity following the initiation of social interaction. Conclusions: VIP interneurons are robustly modulated by acetylcholine, and this modulation is consistently altered in two distinct mouse models of autism. Furthermore, VIP interneurons play a major role in modulating social interaction. VIP interneurons thus may contribute to abnormal social behavior in autism and represent a novel therapeutic target. Supported By: SFARI, NSF Keywords: acetylcholine, Autism, interneurons, social behavior, optogenetics
337. Neuropsychiatric Profiles of Children and Adolescents with Hypothalamic Hamartomas Georgina Corbet Burcher1, Elisabetta Caredda2, Robert Wilkinson2, Sophie Bennett2, Helen Cross3, Martin Tisdall2, Helen Spoudeas2, Sue Harrison2, Sophia Varadkar2, and Isobel Heyman3 Imperial College London, 2Great Ormond Street Hospital, London, 3University College London 1
Background: Hypothalamic hamartomas are rare brain malformations characterised by a clinical syndrome of
S138
seizures, central precocious puberty, behavioral, emotional and cognitive difficulties. Psychiatric symptoms often present the greatest burden of morbidity for patients and families. Due to the rarity of the disease, the heterogeneity of the presentation, and the multifactorial aetiology, prognosis is varied and management strategies are yet to be standardised. Methods: The notes of 46 pediatric cases with hypothalamic hamartomas were examined retrospectively. Demographics, psychiatric symptoms, cognitive functioning, epileptic profiles, and pubertal status were recorded. ICD-10 codes for psychiatric disorder were assigned to applicable cases. Results: 61% of cases were male. The mean age at diagnosis was 4.2 years (0-14 years). 71.7% of the cases met criteria for $ 1 ICD-10 Axis 1 psychiatric disorder. Attention Deficit Hyperactivity Disorder, Generalized Anxiety Disorder and Autism Spectrum Disorder were most frequent. 46% experienced characteristic rage attacks. 50% had some degree of intellectual disability, most commonly mild. 63% of cases experienced seizures, most commonly gelastic in nature. 40% of cases had precocious puberty. Conclusions: This data set represents one of the largest in the pediatric hypothalamic hamartoma literature. A significant proportion of cases have psychiatric disorders and intellectual disability. These presenting features are a product of numerous aetiological factors. The direct brain-behaviour effects from disrupted hypothalamic functioning, possible epileptic encephalopathy resulting from refractory seizures and impact of antiepileptic medications are all contributory. These findings also provide insight into the pathoaetiology of other neuropsychiatric disorders where hypothalamic dysfunction has been implicated. Keywords: hypothalamic hamartoma, seizures, aggression
338. Enabling Precision Psychiatry through ‘omics’: From Biomarkers to Biological Pathways Brisa Fernandes1 and Michael Berk2 1 Deakin University, School of Medicine, 2Deakin University, IMPACT Strategic Research Centre, School of Medicine, Faculty of Health, Geelong
Background: Schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) are severe mental disorders regarded as syndromes and defined by a clustering spectrum of signs and symptoms. Thus far, there is no single defining clinical or pathological hallmark for any of those disorders, and their symptoms profiles overlap with each other in what is considered the schizoaffective spectrum. The lack of knowledge about their neurobiology hampers the identification of biomarkers, which could guide risk, prognosis, clinical diagnosis and therapeutic decisions. Methods: We performed a systematic review of all studies employing proteomics or metabolomics in peripheral blood of persons with SZ, BD, or MDD compared to controls and extracted all differentially expressed proteins. After, we derived the involved biological pathways according to which altered proteins were unique to SZ, BD, or MDD and to which were shared using Ingenuity Software.
Biological Psychiatry May 15, 2017; 81:S1–S139 www.sobp.org/journal