Molecular Basis of Neuropsychiatric Disorders (ANAT0012)
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Molecular Basis of Neuropsychiatric Disorders (ANAT0012) Notes
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Molecular Basis of Neuropsychiatric Disorders (ANAT0012)
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University College London (UCL)
Explore Molecular Basis of Neuropsychiatric Disorders at UCL. Uncover the intricate facets of schizophrenia, genetics, and the neurobiology of mental diseases. Delve into the realms of drug addiction, depression, severe OCD, learning, memory, anxiety, trauma, dissociation, and the epigenetic dimens...
Molecular Basis of Neuropsychiatric Disorders (ANAT0012)
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Neurobiology of Schizophrenia
Schizophrenia
• Features
o Schizophrenia affects the most basic human processes of perception, emotion, judgement
o Heterogenous syndrome
o No single defining symptom or sign
o Currently cannot be identified with a diagnostic laboratory test
o Diagnosis:
▪ Psychotic phenomena – hallucinations, delusion and thought disorder – after other causes of
psychosis have been excluded
• Symptoms
o Positive symptoms – characterised by abnormal thoughts, perceptions, language and behaviour
▪ Include
• Delusions
o False beliefs or thoughts with no basis in reality
• Hallucinations
o Disturbances of sensory perception – e.g. seeing, hearing, feeling things that
are not there
o Auditory and visual hallucinations
• Disorganised thinking / speech
o Jumping from topic to topic, slipping off topic, responding to questions with
unrelated answers, speaking incoherently
• Disorganised behaviour
o Problems performing goal directed daily activities like meal planning and
maintaining personal hygiene, child-like actions, unprovoked agitation
• Lack of insight
o Individuals unaware that their delusions or hallucinations aren’t real –
distressing
▪ Positive symptoms can also be characterised as symptoms of psychosis
• Symptoms of psychosis
o Delusions
o Hallucinations
o Disorganised thinking/ speech
o Disorganised behaviour
o Lack of insight
• Causes of psychosis
o Schizophrenia – more likely to have persecutory delusions
o Bipolar disorder – during episodes of mania + more likely to have grandiose
delusions
o Severe stress/anxiety
o Severe depression
o Postnatal psychosis – 1:1000
o Lack of sleep
o Encephalitis
o Substance misuse
o Can also occur in several medical conditions – AD, PD, malaria,
hypoglycaemia, MS, brain tumour
o Negative symptoms – characterised by restrictions in range and intensity of emotional expression,
communication, body language and interest in normal activities
▪ Blunted (flat) effects
,Neurobiology of Schizophrenia
• Decreased emotional expressiveness, unresponsive immobile facial appearance,
reduced eye contact and body language
▪ Alogia
• Reduced speech, responses are curt and detached, speech may be less fluid
▪ Avolition
• Lacking motivation, spontaneity, initiative
o E.g. sitting for length periods or ceasing to participate in work or daily
activities
▪ Anhedonia
• Lacking pleasure or interest in activities that were once enjoyable
o Cognitive symptoms
▪ Subtle cognitive problems are increasingly recognised as central to the disease
▪ Include
• Impairments in attention, working memory, learning, verbal fluency, motor speed,
executive functions
o Poor working memory
▪ Linked to dysfunction of the dorsolateral prefrontal cortex
▪ Even patients with good performance are inefficient in their use of
prefrontal networks
▪ Cognitive deficits are relatively stable + already apparent in first-episode patients
▪ Leads to impairment of skills and diminished functional capacity
▪ Also found in biological relatives of subjects
• Suggesting that the aspect of cognitive impairment in SCZ – may be under genetic
control
▪ Cognitive tests could be used in clinical trials and genetic testing
• Diagnosing schizophrenia
o Criteria for schizophrenia – from the diagnostic and statistical manual of mental disorders 5th edition
(DSM5)
▪ A
• 2 or more of the following symptoms for >1 month unless treated successfully –
include:
o Delusions, hallucinations, disorganised speech, disorganised or catatonic
behaviour, + negative symptoms – such as affective flattening or loss of
initiative
▪ B
• Level of functioning is significantly decreased in work, personal relationships, and/or
personal care
▪ C
• Symptoms of the disorder last >6 months
▪ D
• Exclusion of schizo-affective disorder, unipolar and bipolar effective disorder
▪ E
• Symptoms cannot be attributed to the use of drugs or medication, or to a somatic
disorder
▪ F
• In the case of pre-existing autism spectrum disorder – at least 1 month with
prominent hallucinations or delusions
• Treating schizophrenia (psychosis) by targeting the dopamine pathway
o Dopamine hypothesis of SCZ
▪ Derived in part from the discovery of anti-psychotics in the 50s
▪ D2 dopamine receptor is the main target of antipsychotics
,Neurobiology of Schizophrenia
o First generation anti-psychotics (1950s)
▪ Include
• Chlorpromazine
• Haloperidol
• Perphenazine
▪ Extrapyramidal side effects include – tremor, rigidity, dystonia, tardive dyskinesia –
nigrostriatal DA system
▪ Rapid onset of action
▪ Dose-dependency
• Leads to parkinsonian side effects at high doses
▪ Primary mechanism of action is D2 dopamine receptor blockade
• Dopamine receptors in the brain are GPCRs
o D2 dopamine receptor
▪ Coupled to inhibitory G-protein Gi = inhibits an enzyme adenylate
cyclase
o Potency of first-generation antipsychotics in treating positive symptoms =
strongly correlated with their affinity for D2 dopamine receptors
o Second generation anti-psychotics – atypical anti-psychotics
▪ Risperidone
• Less likely to cause EPS + tend to also act on serotonin receptors as well
▪ Clozapine
• Also act on serotonin (target 5HT2A)
• Can be used in treatment resistant individuals
• Less side EPS – but other serious side effects
• Dysregulated neurotransmitter systems in schizophrenia
o Dopamine
▪ Importance neurotransmitter involved in:
• Movement, emotional regulation, reward, cognition
▪ 5 dopaminergic pathways in humans
• Nigrostriatal, mesolimbic, mesocortical, tuberinfundibular, thalamic
o Mesolimbic and mesocortical dopaminergic pathways = most relevant to the
pathophysiology of schizophrenia
▪ Mesolimbic pathway
• Originate in dopamine-producing cells in the central
tegmental area (VTA) in the midbrain → dopaminergic
neurons second afferents to the striatum, hippocampus,
amygdala
• Increased dopaminergic activity in the mesolimbic pathway
= accounts for the positive symptoms
▪ Mesocortical pathway
• Originates in the VTA → projects throughout the cortex –
including the PFC
• Decreased dopaminergic activity in the mesocortical
pathway = may account for the negative symptoms and
cognitive impairments
▪ Dopamine receptors
• GPCRs
• 5 subtypes of the dopamine receptor
o D2 and D4 are most relevant to schizophrenia
• Primary mechanism of therapeutic action of antipsychotics = blockade of D2
receptors
, Neurobiology of Schizophrenia
• Blockade of D2 receptors in the mesolimbic pathway → produces antipsychotic
effects
• Blockade of D2 receptors in the nigrostriatal pathway → produces extrapyramidal
symptoms
▪ Atypical antipsychotics still block D2 receptors → producing antipsychotic effect
• But also block other receptors – 5HT2A receptors → attenuateing the neurological
side effects
o Antagonist at 5HT2A receptors → enhances striatal dopamine release = may
confer some antipsychotic effects
▪ Models of schizophrenia using animals with dysregulated dopaminergic neurotransmission
• After release from presynaptic terminals – dopamine is cleared from the extracellular
space by a membrane-spanning dopamine transpoter (DAT) – which plays a critical
role in the regulation of dopamine levels
o DAT knockout mice → have increased brain dopamine levels, hyperactivity,
deficits in sensory gating
▪ Amphetamine or L-DOPA administration can mimic symptoms of schizophrenia
▪ Antipsychotic drugs alleviate some of the symptoms of amphetamine psychosis
▪ Excess dopamine release occurs in schizophrenics
▪ Increased dopamine receptor binding – specifically D2 receptors in patients brains and scans
o Glutamate
▪ Dissociative anaesthetics – phencyclidine (PCP), ketamine = non-competitive antagonist at
the NMDA subtype of glutamate receptors
• Can produce psychotic + cognitive abnormalities reminiscent of SCZ in humans
o NMDA receptor hypofunction – may contribute to the cognitive symptoms of
SCZ
• Decreased neurotransmission at NMDA receptors in SCZ
• May be a loss of synaptic connectivity in SCZ
o Glutamate receptors are enriched on the postsynaptic side on dendritic
spines (protrusions from the dendrite)
▪ There may be a loss of dendritic spines in SCZ
• Seen in postmortem studies
o Overall decrease in density of postsynaptic elements
– particularly in cortical areas
• Seen in living patients – decreased synaptic connectivity
o Loss of excitatory synapses in individuals with SCZ
▪ Synaptophysin is a marker of synapse
• Its mRNA expression is reduced in the hippocampus,
superior temporal gyrus (STG), visual cortex – from
individuals with schizophrenia
▪ Vesicular glutamate transpoter-1 (VGLUT1) is a synaptic protein –
concentrates glutamate into synaptic vesicles
• Its mRNA expression is reduced in the hippocampus and
DLPFC
▪ Data indicates that a loss of glutamatergic synapses occurs in
multiple brain areas in SCZ
• Changes in brain structure
o Changes in brain volume in schizophrenia
▪ Ventricular enlargement
• Lateral and third ventricular enlargement
▪ Medial temporal lobe (hippocampal formation, subiculum, parahippocampal gyrus) volume
reduction
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