Gene-environment interactions modulating cognitive and affective endophenotypes in mice

Transcription

1 12 th International Conference on Cognitive Neuroscience, Brisbane, 29th July 2014 Gene-environment interactions modulating cognitive and affective endophenotypes in mice Anthony Hannan Florey Institute of Neuroscience and Mental Health University of Melbourne

2 Disorders with high genetic loads (e.g. HD) Disorders with complex polygenic & environmental loads (e.g. schizophrenia, depression, autism, dementia) Disorders with high environmental loads (e.g. stroke) GENETIC FACTORS monogenic polygenic (Genome) ENVIRONMENTAL FACTORS mental/physical activity stressors, toxins, diet ( Envirome )

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4 Tandem repeat polymorphisms and mutations Hannan, 2010

5 Huntington s Disease Fatal neurodegenerative disorder with autosomal dominant inheritance Psychiatric symptoms (e.g. depression), cognitive deficits (culminating in dementia), and a movement disorder (e.g. chorea) Caused by a CAG/glutamine repeat expansion in huntingtin (HD Collab. Research Group, 1993, Cell) which is most toxic to specific neuronal populations in the cerebral cortex and striatum (Wang et al., 2014, Nature Med.)

6 huntingtin protein huntingtin mrna (QQQQQ) n+x Abnormal protein cleavage, folding, multimerization Altered gene expression, trafficking, signaling, homeostasis, etc. Toxic gain-of-function, abnormal molecular interactions (CAGCAGCAGCAGCAG) n+x PATHOLOGICAL PLASTICITY? CELLULAR DYSFUNCTION COGNITIVE & PSYCHIATRIC SYMPTOMS MOTOR SYMPTOMS huntingtin gene

7 Transgenic HD mice R6/1 mice expressing human exon 1 transgene encoding expanded polyglutamine in the huntingtin N-terminal fragment (Mangiarini et al., 1996, Cell) Progressive neurodegenerative phenotype, including affective, cognitive and motor deficits HD WT

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9 Somatosensory discrimination learning test Mazarakis et al., 2005, J. Neurosci.

10 Motor presymptomatic HD mice have a deficit in somatosensory discrimination learning Genotype 10 Positive HD Negative HD Trials Mazarakis et al., 2005, J. Neurosci.

11 Barrel Cortex 2DG Right/Left Areas Histology

12 Motor presymptomatic HD mice have a deficit in experience-dependent barrel cortex plasticity WT HD Mazarakis Mazarakis et al., et J. al., Neurosci. 2005, J. (in Neurosci. press)

13 Spatial learning and memory in the Morris water maze Spatial navigation task Repeated daily trials to locate platform Probe trial: no platform present Frequency, duration and latency to the quadrant and platform can be used as measures of memory acquisition

14 A GSK-3b signaling abnormality in the cerebral cortex of HD mice correlates with cognitive deficits WT HD WT HD Lim et al., 2014, Hum. Mol. Genet.

15 Molecular and cellular mediators of cognitive deficits Abnormal protein interactions (toxic gain of function) GSK-3b b-catenin, CREB (Q) n+x Huntingtin protein Gene expression (e.g. GluRs, BDNF, etc.) (CAG) n+x Cellular plasticity deficits (adult neurogenesis & synaptic plasticity) Huntingtin gene COGNITIVE DEFICITS & DEMENTIA

16 Time (sec) HD mice develop a sexually dimorphic depression-like behavioural endophenotype by 12 weeks of age Novelty suppressed feeding test (NSFT) Antidepressants with clinical efficacy rescue this behavioural sign C HD WT 200 NSFT - Latency to feed * 50 0 Female Male Pang et al., 2009, Hum. Mol. Genet.

17 Depression-like behaviour in female HD mice is rescued by chronic administration of an SSRI Sacharin-preference test (SPT) of anhedonia Ɨ * Renoir et al., 2012, BJP

18 Disease onset and progression in the R6/1 transgenic mouse model of HD Onset of molecular and cellular deficits? Age (weeks) Onset of affective and cognitive abnormalities (Mazarakis et al., 2005, J. Neurosci. Pang et al., 2008, Hum. Mol. Genet.) Decreased cortical and striatal volume (van Dellen et al., 2000, Nature) End-stage disease/death (Mangiarini et al., 1996, Cell) Onset of motor deficits (van Dellen et al., 2000, Nature) Onset of neuronal cell death (Turmaine et al., 2000, PNAS)

19 Environmental enrichment enhances activity levels Nithianantharajah & Hannan, 2006, Nature Rev. Neurosci.

20 Environmental enrichment delays disease onset a Percentage with phenotype (failing rod test) Standard housed HD Environmentally enriched HD Wild-type Age (days) Van Dellen et al., 2000, Nature Subsequent studies exploring environmental enrichment, cognitive and/or motor stimulation in HD mice: Hockly et al., 2002 ( minimal enrichment ); Spires et al., 2004; Schilling et al., 2004; Lazic et al., 2006; Pang et al., 2006, 2009; Kohl et al., 2007; van Dellen et al., 2008; Nithianantharajah et al., 2008; Benn et al., 2010; Zajac et al., 2010; Renoir et al., 2011; Wood et al., 2011; Du et al., 2012

21 Evidence for environmental modifiers in clinical HD Wexler et al.; US-Venezuela Collaborative Research Project, 2004, PNAS - Analysis of large Venezuelan kindreds showing that the remaining variance not explained by CAG repeat length has a major environmental component Trembath et al., Delatycki, 2010, Mov. Disorders - Retrospective study of Australian & New Zealand families indicating that passivity (reduced activity) is a risk factor contributing to earlier age of HD onset Twin studies provide further evidence (although somatic CAG repeat instability and stochastic epigenetic variability may also play a role)

22 (Q) n+x? ENVIRONMENTAL MODULATORS MOLECULAR MEDIATORS huntingtin protein?? SELECTIVE CELLULAR DYSFUNCTION (CAG) n+x MOTOR, COGNITIVE & PSYCHIATRIC SYMPTOMS huntingtin gene

23 Hypothesised mechanisms mediating the beneficial effects of environmental enrichment Gene expression? (experience-dependent regulation) Cellular plasticity? (neurogenesis & synaptic plasticity) huntingtin (Q n+x ) Abnormal protein interactions? EE?? Altered gene expression Epigenetics?

24 Mean # errors Environmental enrichment delays onset of hippocampal-dependent cognitive deficits in HD mice ERRORS WTNE WTE HDNE st 2nd 2nd to last Last Block of 5 trials ** HDE Barnes circular maze Nithianantharajah et al., 2008, Neurobiol. Dis.

25 Time (sec) A depressive-like behavioural endophenotype is rescued by environmental enrichment Performance in the forced-swim test (FST) responds to clinically effective antidepressants A 200 FST performance of female mice * HD WT *** 50 0 Standard housed Environmental Enrichment Pang et al., 2009, Hum. Mol. Genet.

26 Parsing the components of environmental enrichment: Can enhanced voluntary physical exercise alone induce beneficial effects? Nithianantharajah & Hannan, 2006, Nature Rev. Neurosci.

27 Abnormal stress response in female HD mice is ameliorated by increased voluntary exercise *** Wheeling running delays onset of cognitive, affective and motor deficits in HD mice: Pang et al., 2006; van Dellen et al., 2008; Renoir et al., 2012 Renoir et al., 2013, J. Physiol.

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29 Assessing short-term spatial memory in the Y-maze TRAINING TRIAL TEST Intertrial interval (e.g. 1 hr) e.g. 10 min e.g. 5 min

30 Stress as a modulator of pathogenesis: Elevated stress hormone accelerates cognitive deficits Y-maze Experience-dependent HPA axis dysfunction in HD mice: Du et al., 2012, Transl. Psychiatry Mo et al., 2014, Neurobiol. Dis.

31 PHARMACOLOGICAL MODULATORS (e.g. ENVIROMIMETICS ) (Q) n+x ENVIRONMENTAL MODULATORS MOLECULAR MEDIATORS huntingtin protein? SELECTIVE CELLULAR DYSFUNCTION (CAG) n+x MOTOR, COGNITIVE & PSYCHIATRIC SYMPTOMS huntingtin gene

32 Potential mechanisms mediating brain and cognitive reserve (BCR) Cognitive stimulation Genetic/ environmental modifiers Molecular mediators BCR Cellular mediators Systems effects Sensory stimulation Epigenetics (e.g. DNA methylation, histone modifications, regulatory RNA) Activity-dependent gene expression (e.g. neurotrophins) Protein processing and trafficking Neurogenesis Synaptic plasticity Synaptogenesis Gliogenesis Angiogenesis Network plasticity Efficiency of information processing and storage Connectivity and functional redundancy Physical activity Nithianantharajah & Hannan, 2009, Prog. Neurobiol.

33 GENETIC MEDIATORS EMBRYONIC BRAIN DEVELOPMENT ENHANCED MENTAL/PHYSICAL ACTIVITY BRAIN MATURATION & EXPERIENCE-DEPENDENT PLASTICITY OTHER ENVIRONMENTAL FACTORS (e.g. stress) NEUROPROTECTION VIA BCR DYSFUNCTION IN SPECIFIC NEURAL SYSTEMS FUNCTIONAL COMPENSATION FAILURE TO COMPENSATE HEALTHY BRAIN MATURATION & AGING THERAPEUTICS (e.g. ENVIROMIMETICS) BRAIN DISORDER SYMPTOMATOLOGY Nithianantharajah & Hannan, 2009, Prog. Neurobiol.

34 Florey Institute of Neuroscience and Mental Health, University of Melbourne Terence Pang Thibault Renoir Jess Nithianantharajah (Edinburgh) Xin Du Emma Burrows Caitlin McOmish (Columbia University) Michelle Zajac Mark Ransome Christina Mo (Chicago) Annabel Short Dean Wright Laura Gray (Deakin University) Jake Rogers Faith Lamont Mari Kondo (Johns Hopkins University) Shlomo Yushuren Lily Laskaris Elizabeth Manning (Pittsburgh) Andrew Argyropoulos Yanting Choong Chris Barkus (Oxford) Alex Eastwood Lavie Vo Ariel Zeleznikow-Johnston Pathology, Univ. Melb. Nastasia Lim, Peter Crouch INSERM, Paris Laurence Lanfumey University of Oxford Colin Blakemore NHMRC, ARC

35 Gene-environment interactions and adult neurogenesis Li et al., 2004 Lazic et al., 2004 Grote et al., 2005 Gil et al., 2005 Philips et al., 2005 Pang et al., 2008 Kempermann et al., 1997 Van Praag et al., 1999 Malberg et al., 2000 Lazic et al., 2006 Pang et al., 2006 Pang et al., 2008 Genetic & environmental factors (e.g. HD, 5-HT signaling, BDNF, glucocorticoids, stress ) Environmental enrichment, exercise, SSRIs (e.g. fluoxetine, sertraline) Decreased neurogenesis Depression/Cognitive deficits? Increased neurogenesis Antidepressant/Cognitive effects?

36 Percentage duration Wheel running delays the onset of a short-term spatial memory deficit in HD transgenic mice 14 week Y-maze Control and RW Duration * * * Home Familiar Novel WT HD WT RW HD RW Running delays onset of cognitive, affective and motor deficits in HD mice: van Dellen et al., 2008; Renoir et al., 2012 Pang et al., 2006, Neuroscience