Molecular biology of the the brain and mental disorders

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Curtis Perkins
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1 Molecular biology of the the brain and mental disorders

2 Uniqueness of human brain 1 DNA Environment Disorders of brain: neurology, neurosurgery Disorders of mind: psychiatry, psychology

2 Symptoms & Disease The symptom is never the disease itself!

There are hardly any symptoms that occur in only a single disease -

group of symptoms was called pectoral disease before 1900.

TBC, asthma, or cancer ELIMINATION OF SYMPTOMS DOES NOT MEAN TO

3 2 Symptoms & Disease The symptom is never the disease itself! - The real cause of most of the diseases cannot be directly seen - There are hardly any symptoms that occur in only a single disease - However, certain symptoms happen together: : e.g. chest ache, cough, loss of weigh, fever, asphyxia, anaemia - - This group of symptoms was called pectoral disease before However, there is no pectoral disease, it can be: bronchitis, TBC, asthma, or cancer ELIMINATION OF SYMPTOMS DOES NOT MEAN TO CURE THE DISEASE - Hypothesis and concrete knowledge: we only have hypotheses for many of the diseases, however, we often can cure them without knowing the precise cause

4 Molecular biology of mental disorders 1. Anxiety 2. Depression 3. Schizophrenia 4. Suicide

5 Treatment of mental disorders 3 1. Psychotherapy (talk therapy) Psychoanalysis theory 2. Biological psychiatry (medicament therapy)

6 The role of neurotransmitters 4 Noradrenalin Serotonin alertness motivation anxiety mood, emotions cognitive functions sex, aggression, appetite impulsivity drive Dopamine

7 5 Anxiety Types: 1. Generalized anxiety disorders 2. Panic disorder 3. Phobia disorders - agoraphobia (60%) - specific phobias (17%) - social phobia (8%)

8 Anxiety 6 Molecular biological background HPA axis Stress hypothalamus CRH Anterior pituary gland ACTH prefrontal cortex Adrenal gland cortizol amigdala hippocampus vese Physiological changes controlling the fight or flight response + HPA axis - + cortizol HPA: hypothalamic-pituitary-adrenal axis

Amygdala Increasing CHR Increasing ACTH Increasing

Anxiety Hippocampus Decreasing CHR Decreasing ACTH

hippocampál inhibition 7 Increasing stress

9 Amygdala Increasing CHR Increasing ACTH Increasing cortisol Increasing stress Hyperakctive amygdala Anxiety Hippocampus Decreasing CHR Decreasing ACTH Decreasing cortisol Decreasing stress Decreasing hippocampál inhibition 7 Increasing stress Increasing cortisol Neuron damage in the hippocampus Increasing cortisol

10 Anxiety 8 barbituate GABA benzodiazepine Medication: 1. psychotherapy 2. medicament - benzodiazepine - SSRIs GABA A receptor GABA-gated Cl - channel GABA GABA + benzodiazepine 1 s 5 mv

background: Allele 1: Allele 2: valine 4-fold

density hesitation methionine An individual

anxiety, negative thinking, neurotic Such

connection and therefore they can concentrate

11 The worry gene COMT gene catechol-o-methyltranspherase Genetic background: Allele 1: Allele 2: valine 4-fold enzyme activity low dopamine higher neuron density hesitation methionine An individual with two low activity COMT genes: - worry, anxiety, negative thinking, neurotic Such animals have a higher density of neural connection and therefore they can concentrate much better: a compromise: better cognitive function, higher anxiety level. The level of anxiety: startle reflex

12 9 Depression 1. Major depression 2. Bipolar disorder: alteration of depression and mania Van Gogh Beethoven

Roland Kuhn Depression Monoamine hypothesis 1970 10 Proofs of monoamine hipothesis: 1.

Isonicid (anti-tbc drug): causes euphoria - MAO inhibitor: catecholamine hypothesis Julius Axelrod 3.

reuptake inhibitor: serotonin hypothesis Sir Bernard Katz Shortages of monoamine hypothesis : 1.

13 Roland Kuhn Depression Monoamine hypothesis Proofs of monoamine hipothesis: 1. Reserpin (anti-hypertension drug): causes depression - monoamine release from synaptic vesicles 2. Isonicid (anti-tbc drug): causes euphoria - MAO inhibitor: catecholamine hypothesis Julius Axelrod 3. Imipramin (modification of a sleeping drug): effective against depression - a norepinephrine and serotonin reuptake inhibitor: serotonin hypothesis Sir Bernard Katz Shortages of monoamine hypothesis : 1. The antidepressant effects of above drugs appear only after weeks 2. Those drugs (e.g. cocaine), which raise a norepinephrine level at the synaptic cleft display no antidepressant effects

14 Depression 11 Charles Nemeroff Diathesis-stress hypothesis Genetic predisposition + stress effect on HPA axis prefrontal cortex amygdala hippocampus + HPA axis - + cortizol Genetic factors Environmental factors

15 Depression 11 Charles Nemeroff Diathesis-stress hypothesis Genetic predisposition + stress effect on HPA axis prefrontal cortex amygdala hippocampus + HPA axis - + cortizol + Raphe nucl Serotonergic cells maternal care

16 Depression Treatment Electroconvulsive therapy 2. Psychotherapy 3. Antidepressants (1) Tricyclic drugs: NE and 5-HT (serotonin) reuptake inhibition (2) SSRIs: 5-HT reuptake inhibition (3) MAO inhibitors: inhibit the enzymatic degradation of NE and 5-HT

Antidepressants 13 Noradrenerg neuron Anti-depressant effect Depressant effect Inhibition of synthesis Inhibition of synthesis Inhibition of vesicular storage Deaminated products DRUG

17 Antidepressants 13 Noradrenerg neuron Anti-depressant effect Depressant effect Inhibition of synthesis Inhibition of synthesis Inhibition of vesicular storage Deaminated products DRUG EFFECT MAO inhibition MAO inhibitors Stimulation of release Receptor stimulation Receptor inhibition receptors reuptake pump Inhibition of reuptake COMT inhibition enzyme Tricyclic drugs

18 Depression NORADRENERGIC PATHWAYS 14 Thalamus Cingulum Toward hippocampus Cortex Hypothalamus Amygdala Hippocampus Lateral tegmental NE cell system Locus ceruleus Cerebellum cortex

19 Antidepressants 15 DRUG EFFECT Serotonergic neuron Inhibition of synthesis Anti-depressant effect Depressant effect Decay product Inhibition of vesicular storage Inhibition of autoreceptors MAO inhibition MAO inhibitors autoreceptor Receptor stimulation receptor reuptake pump Inhibition of reuptake SSRIs + Tricyclic drugs

20 Depression SEROTONERGIC PATHWAYS 16 Thalamus Cingulum Toward hippocampus Cortex Amygdala Hippocampus Rostral raphe nucleus Caudal raphe nucleus Cerebellum cortex

21 The gene of depression serotonin SERT gene serotonin transporter Cingulate cortex promoter ORF amygdala

22 Schizophrenia Brains of identical twins 17 John Forbes Nash Russel Crow: A Beautiful Mind Genetic disease In identical twins: 50% penetrance High ventricle-brain ratio

23 DOPAMINERGIC PATHWAYS Schizophrenia Dopamine hypothesis Striatum 18 MESOLIMBIC TRACT Frontal lobe Substantia nigra MESOCORTICAL TRACT NIGROSTRIATAL TRACT Ventral tegmental area

24 Dopaminergic neuron DRUG EFFECT Schizophrenia Dopamine hypothesis Dopamine hyperactivity in the behavior centers of brain Inhibition of synthesis Stimulation of synthesis Decay product Anti-psychotic effect Psychotic effect 19 Stimulation of release MAO inhibitors Inhibition of release Inhibition of autoreceptors Receptor inhibition Antipsychotics D2 receptor receptors reuptake pump enzyme Inhibition of reuptake cocaine, amphetamine

25 Schizophrenia 20 Glutamate hypothesis NMDA receptor (ionotropic receptor) PCP: angel dust - hallucinogenic

26 Schizophrenia Glutamate hypothesis Presynaptic glutamate terminal Metabotropic glutamate receptor agonist - Eli Lilly, 2007 Clinical Phase LY Presynaptic dopaminergic terminal Glia Spiny neuron

27 22 Suicide Polymorphism in the SERT gene DNA Coding regions Non-coding regions protein

28 Molecular biology of brain disorders 1. Prion betegség 2. Trinucleotide repeat disease 3. ALS 4. Parkinson s disease 5. Alzheimer s disease

29 23 Prion disease The infectious form of prion disease is caused by a protein and not by an organism with genetic material!!! 1. Human CJD, vcjd, kuru 1. Sporadic 2. Familial 3. Acquired 2. Animal BSE, scrapie

30 24 Normal protein conversion Disease protein Prion disease aggregation Chromosome 20 Stanley B. Prusiner PrP C PrP SC PK sensitive PK resistant

31 25 Trinucleotide repeat diseases Neurological diseaes: DISEASE GENE (protein) REPEAT 1. Huntington s disease IT15 (huntingtin) (CAG)n (Gln) 2. Dentatorubral-pallidoluysian atrophia DRPLA (Atrophin 1) (CAG) n (Gln) 3. Dystrophia myotonica DM (CTG)n (Leu) 4. Fragile X syndrome FMR1 (CCG)n (Pro) 5. Friedreich ataxia FXN (GAA)n (Gln) 6. Kennedy s disease SBMA, AR (androgén receptor gén) (CAG)n (Gln) 7. Spinocerebellar ataxia TBP (CAG)n (Gln) - 1, 2, 3, 6, 7, 17 típusai: : ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7

full penetrance IT15 (huntingtin) (CAG)n glutamine INHERITANCE AFFECTED BRAIN

32 Huntington s Disease 26 GENETIC BACKGROUND chromosome 4 GENE (protein) triplet repetition amino acid CAG < 35 normal reduced penetrance 40 full penetrance IT15 (huntingtin) (CAG)n glutamine INHERITANCE AFFECTED BRAIN REGIONS Basal ganglion Mutant gene carrying sperm Cortex Autosomal dominant inheritance

33 Huntington s Disease 27 CELLULAR MECHANISM

34 28 ALS disease (Amyotrophic Lateral Sclerosis) Steven Hawking Motor neurons normal diseased The degrading effect of SOD-1 can lead to apoptosis

35 Parkinson s disease 29 Mohammad Ali & Michal J Fox The Dopamine hypothesis Dopamine pathways Nigrostriatal pathway

36 Parkinson s disease 30 The Dopamine hypothesis Normal brain Parkinson brain Normal braon Parkinson brain Thalamus Basal ganglion Basal ganglion Nucleus subthalamicus MIDDLE BRAIN Direct pathway Indirect pathway Normal neuron Parkinson neuron

37 31 Parkinson s disease Dopaminergic neuron Decay product DRUG EFFECT MAO inhibitors reuptake pump Dopamin agonists Receptor stimulation receptors COMT inhibition COMT inhibitors enzyme

38 Parkinson s disease 32 BRAIN ELECTRODES ALTERNATIV THERAPIES Nucleus subthalamicus STEM CELL THERAPY GAD Thalamus TH Basal ganglion GENE THERAPY Substantia nigra

39 33 Alzheimer s disease Ronald Reagen normal Alzheimer s normal Alzheimer s

40 Alzheimer s disease 34 The amyloid hypothesis The Tau hypothesis

Νευροφυσιολογία και Αισθήσεις

Biomedical Imaging & Applied Optics University of Cyprus Νευροφυσιολογία και Αισθήσεις Διάλεξη 19 Ψυχασθένειες (Mental Illness) Introduction Neurology Branch of medicine concerned with the diagnosis and