The Neurobiology of Au0sm. Computa0onal Psychiatry Seminar HS 14 Isabel Berwian

Transcription

1 The Neurobiology of Au0sm Computa0onal Psychiatry Seminar HS 14 Isabel Berwian

2 Content NeurotransmiFer (Lam et al., 2006) Gene0cs (Klei et al., 2012) Animal models (Schneider, 2010)

3 Why study Neurobiology? Iden0fy underlying deficits à shape e0ological theories à guide pharmacological interven0ons à improve diagnos0c tools

4 Guiding neurobiological research Early start (before age of 3) High co- occurrence with mental retarda0on Abnormal EEGs Higher propor0on of boys affected Evidence for gene0c component in twin studies

5 Difficul0es studying NB of Au0sm Diagnos0c Problems: Heterogeneous syndrome expression Co- occurrence with mental retarda0on Comorbid behavioral problems According to symptoms (DSM- V) vs. syndrome (ICD- 10)

6 Neurotransmission 1)

7 Serotonin 2a) 2b)

8 Serotonin Behavioural effects: mood, ea0ng, arousal, pain sensi0vity, sexual behaviour, hormone release Why interes0ng for au0sm? - Role in percep0on - Effect of acute tryptophan deple0on - Role in neural development

9 Evidence: Serotonin Hyperserotonemia in blood, but no rela0on to symptomology found - possibly due to comorbid mental retarda0on - or lack of matching for pubertal status and race No difference in central serotonergic func0oning Pet studies in au0sm: - decreased synthesis in unilateral frontal cortex a and thalamus and increase in contralateral dentate gyrus (or oppsite pafern) - at age 2 to 5 lower levels of serotonin and increase with age à abnormal developmental regula0on

10 Evidence: Serotonin Gene0cs: unclear evidence concerning the serotonin transporter gene à associated with gene0c heterogeneity SSRIs reduces persevera0ve behaviour

11 Dopamine 4) 3)

12 Dopamine Behavioural effects: cogni0on, motor func0on, reward mechanisms, neuroendocrine regula0on, selec0ve afen0on Why interes0ng for au0sm? - DA blockers reduce hyperac0vity, stereotypes and aggression - Increase DA func0oning in animals à induce similar symptoms à DA neurons might be overac0ve in au0sm.

13 Evidence: Dopamine No clear evidence for peripheral dopaminergic abnormali0es No clear evidence concerning difference of central dopamine levels, BUT possibly related to hyperkinesia and stereotypic behaviour Risperidone decreases irritable behaviours and stereotypic/ compulsive behaviour, also slightly social withdrawal and inappropriate speech

14 Norepinephrine Synthesized from DA Behavioural effects: afen0on, stress response, anxiety and memory Many of these func0ons are impaired in au0sm à inves0gate noradrenergic func0ons in au0sm 5)

15 Evidence: Norepinephrine Peripheral measure reflect central NE 5 out of 7 studies found increased NE concentra0on Inconsistent results concerning excre0on of NE No difference in CSF Explana0on: plasma NE reflects sympathe0c arousal when blood drawing à Probably no effect of NE in au0sm Also no consistent findings rela0ng to drugs

16 Acetylcholine Muscarinic and nico0nic receptors Behavioural effects : ac0on system Abnormal cholinergic neurons in basal forebrain in au0sm and role in cogni0ve abili0es à begin of studying ACh in au0sm 6)

17 Evidence: Acetylcholine Only postmortem studies: - reduced binding in nico0nic receptors in parietal (also muscarinic) and frontal cortex Unclear rela0on to e0ology Treatment with acetylcholinesterase inhibitors: - improvements in irritability, but also symptoms of au0sm and language à Need further studies

18 Oxytocin OXT gene à inac0ve precursor protein (includes neurophysin I.) à oxytocin Projec0ng widely throughout the brain Behavioural effects: maternal behaviour, infant separa0on distress, sexual behaviour and social afachment Interes0ng due to role in social func0oning

19 Evidence: Oxytocin Plasma levels in au0sm: - reduced plasma levels - no correla0on with age - nega0ve rela0on to socializa0on skills à Dysregula0on present but no simple OT deficit model Can possibly be used to treat social impairment

20 Endogenous Opioids affect CNS as neuromodulators (mainly reduces pain) Types - beta- endorphins (mu receptors) - enkephalins (mu and delta receptors) - dynorphins (kappa receptors) Behavioural effects: insensi0vity to pain, affec0ve lability, stereotyped behaviours, reduced socialza0on à Cause similar symptoms as seen in au0sm

21 Evidence: Endogenous Opioids Inconsistent findings concerning levels of beta- endorphins in blood à increased levels might reflect acute stress Inconsistent findings concerning opioid level in CSF à studies not well controlled Opiate antagonists reduce self- injurious behaviour, as well as hyperac0vity and impulsive behaviour in some subjects

22 Cor0sol Glucocor0coid released in response to stress Hypothesis: behavioural disturbance due to chronically elevated stress response and hyperarousal 7)

23 Evidence: Cor0sol No heightened cor0sol levels in plasma, but heightened ACTH levels à acute, but no chronic stress response Abnormal suppression of cor0sol à possibly indicates abnormali0es in 5- HT and DA No clinical trials of medica0ons

24 Glutamate and GABA Widely produced and effects widely spread in CNS Pervasive effect on brain ac0vity and func0on Hypothesis: Au0sm as result of single dysfunc0on with broad repercussions 8)

25 Evidence: Glutamate and GABA GABAergic suppression à s0mula0on of glutamate system: - abnormal cellular development in limbic areas and cerebellum - glutamate ac0vity peak at age of 2 à hyperfunc0onality might lead to neural damage - seizures are common in au0sm - reduced GAD levels in au0s0c children Inconsistent findings in drug trials

26 Summary: NeurotransmiFer Overall disappoin0ng results - but par0ally due to bad designs Areas of future interest: - serotonin - oxytocin - early brain development

27 Need of befer studies Apply strict diagnos0c criteria Control for race and pubertal status Assess central func0oning directly Inves0gate dynamic balance of NT, rather than e.g. eleva0ons

28 Au0sm and Gene0cs Liability due to many genes, rather than just a few Role of de novo genes No replicable common polymorphism Different architecture for simplex and mul0plex families

29 Study: Gene0cs Aim: es0mate variability in liability due to inherited varia0ons Compare simplex and mul0plex families Compare to predic0ons of addi0ve model

30 Results: Gene0cs Simplex families - 40% heritability - addi0ve model confirmed Mul0plex families - 65% heritability - more au0s0c phenotype in rela0ves - more risk variants in fathers - deviates from addi0ve model, possibly due to assor0ve ma0ng No fundamental differences between simplex and mul0plex families

31 Problems with Gene0c Studies Current study: - no informa0on on broad- sense heritability and de novo muta0ons - underes0mate rare inherited varia0ons à only inves0gate addi0ve effects - Differences to twin studies

32 Au0sm and Gene0cs Genome- wide associa0on studies: - only few SNPs of small effect, not replicated à 1000s of SNPs at different loci with small effects à need much larger studies to iden0fy SNPs Higher heritability in au0sm compared to other psychiatric disorders

33 Animal Models Study behavioural defects in context of whole organism Models - predic0ve validity (accurate predic0on) - construct validity (causes) - face validity (symptoms) à Best is mul0dimensional approach

34 Animal Models in Au0sm Should incorporate behavioural symptoms, but also biochemistry and gene0c factors Need to define markers of au0sm - Difficult to replicate e.g. theory of mind Especially need to address socio- behavioural aberra0ons and occurrence before age of 3

35 Animal Models in Au0sm Behavioural Markers Social Interac0on - nose- to- nose contact, aggression Social Communica0on - use olfactory and auditory communica0on Repe00ve, stereotyped paferns of behaviour - motor stereotypes

36 Lesion Models Target amygdala and PFC à reduced social interac0ons or social play Problems with model: - strongly deviates from au0sm on neuroanatomical level

37 Models based on Environmental and Immune Factors Exposure to VPA during embryogenesis - mimic behavioural and neurobiological abnormali0es in au0sm - higher in males and reversible Infec0on with Borna disease Virus - mimic impaired social interac0on and percep0on and loss of Purkinje cells - difficult as infects whole brain

38 Gene0cally induced Models 3 models - induce muta0on in genes regula0ng social behaviour - monogene0c aberra0ons - gene0c muta0ons relevant in loci for au0sm suscep0bility Problem: Au0sm is a polygene0c disorder, not reflected in these models.

39 Overall Summary No clearly iden0fiable deficit on neurobiological level Gene0cs indicate that many small deficits à Au0sm might be defined by many small abnormali0es! To few knowledge to build good animal models

40 Literature Klei, L., Sanders, S.J., Murtha, M.T., Hus, V., Lowe, J.K., Willsey, A.J., et al. (2012). Common gene0c variants, ac0ng addi0vely, are a major source of risk for au0sm. Mol Au0sm 3: 9. Lam, K.S.L., Aman, M.G., and Arnold, L.E. (2006). Neurochemical correlates of au0s0c disorder: a review of the literature. Res Dev Disabil 27: Schneider, T. (2010). Au0sm: Animal Models. (Encyclopedia of Psychopharmacology)

41 Sources of Pictures Pictures were taken from the following websites: 1) hfp://en.wikipedia.org/wiki/neurotransmission 2a) and 2b) hfp:// psy128anxiety/anxiety.ht 3) hfp://en.wikipedia.org/wiki/dopamine 4) hfp://en.wikipedia.org/wiki/tyrosine_hydroxylase 5) hfps:// normal_brain/neuro_path_n 6) hfp://web.campbell.edu/faculty/nemecz/323_lect/ Nitrogen_metabolism/nitrogen_chapter.html 7) Lupin, S. J., McEwen, B. S., Gunnar, M. R. and Heim, C. (2009). Effects of stress throughout the lifespan on the brain, behaviour and cogni0on. Nat Rev Neurosci 10, ) hfp://neuroendoimmune.wordpress.com/2013/07/09/gaba- and- glutamate- the- balancing- act- of- the- nervous- system/