Autism spectrum disorders: neurotrophins enter the dance

Autism spectrum disorders (ASD) is a group of lifelong neurodevelopmental disorders characterized by impairment in social interaction and communication, delayed and disordered language, restricted and stereotypic patterns of behaviour, interests and activities, and onset before 3 years of age

Linking haploinsufficiency of the autism- and schizophrenia-associated gene Cyfip1 with striatal-limbic-cortical network dysfunction and cognitive inflexibility

Impaired behavioural flexibility is a core feature of neuropsychiatric disorders and is associated with underlying dysfunction of fronto-striatal circuitry. Reduced dosage of Cyfip1 is a risk factor for neuropsychiatric disorder, as evidenced by its involvement in the 15q11.2 (BP1–BP2) copy number variant: deletion carriers are haploinsufficient for CYFIP1 and exhibit a two- to four-fold increased risk of schizophrenia, autism and/or intellectual disability. Here, we model the contributions of Cyfip1 to behavioural flexibility and related fronto-striatal neural network function using a recently developed haploinsufficient, heterozygous knockout rat line. Using multi-site local field potential (LFP) recordings during resting state, we show that Cyfip1 heterozygous rats (Cyfip1+/−) harbor disrupted network activity spanning medial prefrontal cortex, hippocampal CA1 and ventral striatum. In particular, Cyfip1+/− rats showed reduced influence of nucleus accumbens and increased dominance of prefrontal and hippocampal inputs, compared to wildtype controls. Adult Cyfip1+/− rats were able to learn a single cue-response association, yet unable to learn a conditional discrimination task that engages fronto-striatal interactions during flexible pairing of different levers and cue combinations. Together, these results implicate Cyfip1 in development or maintenance of cortico-limbic-striatal network integrity, further supporting the hypothesis that alterations in this circuitry contribute to behavioural inflexibility observed in neuropsychiatric diseases including schizophrenia and autism

Genetics update: monogenetics, polygene disorders and the quest for modifying genes

The genetic channelopathies are a broad collection of diseases. Many ion channel genes demonstrate wide phenotypic pleiotropy, but nonetheless concerted efforts have been made to characterise genotype-phenotype relationships. In this review we give an overview of the factors that influence genotype-phenotype relationships across this group of diseases as a whole, using specific individual channelopathies as examples. We suggest reasons for the limitations observed in these relationships. We discuss the role of ion channel variation in polygenic disease and highlight research that has contributed to unravelling the complex aetiological nature of these conditions. We focus specifically on the quest for modifying genes in inherited channelopathies, using the voltage-gated sodium channels as an example. Epilepsy related to genetic channelopathy is one area in which precision medicine is showing promise. We will discuss the successes and limitations of precision medicine in these conditions

A human iPSC-based model to investigate the effects of psychiatric risk gene CACNA1C on neuronal development and network activity

CACNA1C encodes the pore-forming subunit of the L-type voltage gated calcium channel Cav1.2. Genome wide association studies have consistently shown that variation in CACNA1C increases risk for psychiatric diseases, including bipolar disorder, schizophrenia, and autism spectrum disorder (ASD). In addition, de novo mutations in the gene cause Timothy Syndrome (TS), a multi-system disorder with symptoms that include ASD, developmental delay and epilepsy. This thesis investigates the role of CACNA1C on cortical neuronal development and neuronal network activity. CRISPR/Cas9 gene editing was used in human induced pluripotent stem cells (iPSCs) to derive homozygous CACNA1C knockout lines. In addition to this an iPSC line was derived from an atypical TS patient carrying a novel mutation in CACNA1C that was predicted to have a gain-of-function effect. Differentiation of these lines into cortical neurons demonstrated changes to the expression of neuronal markers and rosette numbers following alterations to CACNA1C expression/function. Alterations to CACNA1C also led to changes in the activation of downstream signalling pathways and the expression of enzymes responsible for GABA production. Functional analysis of neuronal network activity showed alterations to the pattern of neuron bursting behaviour in both the knockout and patient lines. These changes could be rescued using pharmacology targeting either L-type calcium channels or GABA-A receptors. Overall, this data demonstrates that CACNA1C plays a role in cortical neuronal development and neuronal network activity. The results suggest that changes to GABAergic signalling may be responsible for the changes seen to neuronal network activity

The kynurenine pathway and the brain: challenges, controversies and promises

Research on the neurobiology of the kynurenine pathway has suffered years of relative obscurity because tryptophan degradation, and its involvement in both physiology and major brain diseases, was viewed almost exclusively through the lens of the well-established metabolite serotonin. With increasing recognition that kynurenine and its metabolites can affect and even control a variety of classic neurotransmitter systems directly and indirectly, interest is expanding rapidly. Moreover, kynurenine pathway metabolism itself is modulated in conditions such as infection and stress, which are known to induce major changes in well-being and behaviour, so that kynurenines may be instrumental in the etiology of psychiatric and neurological disorders. It is therefore likely that the near future will not only witness the discovery of additional physiological and pathological roles for brain kynurenines, but also ever-increasing interest in drug development based on these roles. In particular, targeting the kynurenine pathway with new specific agents may make it possible to prevent disease by appropriate pharmacological or genetic manipulations. The following overview focuses on areas of kynurenine research which are either controversial, of major potential therapeutic interest, or just beginning to receive the degree of attention which will clarify their relevance to neurobiology and medicine. It also highlights technical issues so that investigators entering the field, and new research initiatives, are not misdirected by inappropriate experimental approaches or incorrect interpretations at this time of skyrocketing interest in the subject matter

Linking haploinsufficiency of the autism- and schizophrenia-associated gene Cyfip1 with striatal-limbic-cortical network dysfunction and cognitive inflexibility

Impaired behavioural flexibility is a core feature of neuropsychiatric disorders and is associated with underlying dysfunction of fronto-striatal circuitry. Reduced dosage of Cyfip1 is a risk factor for neuropsychiatric disorder, as evidenced by its involvement in the 15q11.2 (BP1–BP2) copy number variant: deletion carriers are haploinsufficient for CYFIP1 and exhibit a two- to four-fold increased risk of schizophrenia, autism and/or intellectual disability. Here, we model the contributions of Cyfip1 to behavioural flexibility and related fronto-striatal neural network function using a recently developed haploinsufficient, heterozygous knockout rat line. Using multi-site local field potential (LFP) recordings during resting state, we show that Cyfip1 heterozygous rats (Cyfip1+/−) harbor disrupted network activity spanning medial prefrontal cortex, hippocampal CA1 and ventral striatum. In particular, Cyfip1+/− rats showed reduced influence of nucleus accumbens and increased dominance of prefrontal and hippocampal inputs, compared to wildtype controls. Adult Cyfip1+/− rats were able to learn a single cue-response association, yet unable to learn a conditional discrimination task that engages fronto-striatal interactions during flexible pairing of different levers and cue combinations. Together, these results implicate Cyfip1 in development or maintenance of cortico-limbic-striatal network integrity, further supporting the hypothesis that alterations in this circuitry contribute to behavioural inflexibility observed in neuropsychiatric diseases including schizophrenia and autism

Summaries of plenary, symposia, and oral sessions at the XXII World Congress of Psychiatric Genetics, Copenhagen, Denmark, 12-16 October 2014

The XXII World Congress of Psychiatric Genetics, sponsored by the International Society of Psychiatric Genetics, took place in Copenhagen, Denmark, on 12-16 October 2014. A total of 883 participants gathered to discuss the latest findings in the field. The following report was written by student and postdoctoral attendees. Each was assigned one or more sessions as a rapporteur. This manuscript represents topics covered in most, but not all of the oral presentations during the conference, and contains some of the major notable new findings reported

Synaptic Dysfunction in Neurodevelopmental Disorders Associated with Autism and Intellectual Disabilities

The discovery of the genetic causes of syndromic autism spectrum disorders and intellectual disabilities has greatly informed our understanding of the molecular pathways critical for normal synaptic function. The top-down approaches using human phenotypes and genetics helped identify causative genes and uncovered the broad spectrum of neuropsychiatric features that can result from various mutations in the same gene. Importantly, the human studies unveiled the exquisite sensitivity of cognitive function to precise levels of many diverse proteins. Bottom-up approaches applying molecular, biochemical, and neurophysiological studies to genetic models of these disorders revealed unsuspected pathogenic mechanisms and identified potential therapeutic targets. Moreover, studies in model organisms showed that symptoms of these devastating disorders can be reversed, which brings hope that affected individuals might benefit from interventions even after symptoms set in. Scientists predict that insights gained from studying these rare syndromic disorders will have an impact on the more common nonsyndromic autism and mild cognitive deficits

Identification and Characterization of Genetic Components in Autism Spectrum Disorders 2020

The Identification of the Genetic Components of Autism Spectrum Disorders 2020 will be a useful resource for laboratory and clinical scientists, translational-based researchers, primary healthcare providers and physicians, psychologists/psychiatrists, neurologists, developmental pediatricians, clinical geneticists, teachers, special educators, and caregivers involved with individuals who have autism spectrum disorders (ASD), with the goal to translate information directly to the clinical, education and home settings. Other professionals, students at all levels, and families who are interested in this important neurodevelopmental disorder will find this textbook of value by obtaining a better awareness of the causes, testing, and understanding of genetic components leading to autism, and research that may open avenues for treatment with new approaches. This textbook includes nine chapters divided into three sections (clinical, genetics, other) written by experts in the field dedicated to genetics research and clinical care, description, and treatment by generating reviews for ASD and related disorders. These chapters include information on discoveries, risk factors, causation, diagnosis, treatment, and phenotyping with characterization of genomic or genetic factors and the environment, as genetics play an important role in up to 90% of individuals with autism via over 800 currently recognized genes

Study of new potential therapeutic approaches for the Rett syndrome in murine models

Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioural and physiological symptoms. RTT is caused by mutations in either the MECP2 or CDKL5 gene. Currently there is no cure for this devastating disorder. The present thesis investigated the potential therapeutic efficacy of two different molecules on RTT mice carrying mutations in MeCP2 or Cdkl5 gene: LP-211, an agonist of serotonin receptor 7 (5-HT7R) and Cannabidivarin (CBDV), new phytocannabinoid under investigation in the clinical setting, which targets the G protein-coupled receptor 55 (GPR55). Our results demonstrate that LP-211 rescue a wide range of behavioural and brain molecular alterations both in MeCP2 and Cdkl5-mutated mice. New clues on the possible mechanism of LP-211 action are provided. The present thesis also demonstrates that in MeCP2-mutated mice the chronic CBDV treatment rescues many important behavioural alterations; moreover, we suggest a possible mechanism of action for CBDV, proposing brain GPR55 as a new pharmacological target for RTT treatment. Despite further studies are needed to clarify the link between RTT and the serotoninergic and/or the endocannabinoid system, the present thesis suggests innovative targets and two promising pharmacological approaches for the treatment of patients affected by this severe disorder