Lecture 6

• Schizophrenia


  • Affects 1% of population
  • Higher incidence in males
  • Adolescent onset
  • Developmental disorder — changes occur early
• Symptoms of schizophrenia


  • Psychosis
  • Positive symptoms
  • Negative symptoms
  • Cognitive deficits
• Psychosis


  Thought disorder characterised by disturbances of reality, impaired cognitive function and inappropriate affect
• Diseases associated with psychosis


  • Schizophrenia
  • Dementia
  • Depression
  • Drug/alcohol abuse
  • Cannabis use
• Positive symptoms


  • Hallucinations - mainly auditory
  • Delusions of grandeur, persecution, etc
  • Thought disturbences
  • Bizzare behaviour
• Negative symptoms


  • Social withdrawal
  • Flat affect
  • Anhedonia
  • Reduced motivation
  • Alogia
• Cognitive deficits


  • Memory + executive function
  • Sensory processing
• Diagnosis of schizophrenia (DSM-5 criteria)


  • Two or more symptoms lasting at least 1 month
  • Delusions
  • Hallucinations
  • Disorganised speech
  • Disorganised catatonic behaviour
  • Negative symptoms
• Genetic risk factors for schizophrenia


  • Monozygotic twins 48% lifetime risk of developing schizophrenia
  • Genetic variation cause change in structure of protein or amount of protein
  • Schizophrenia - not one gene + not simple inheritance
• Genes involved in schizophrenia


  • Developmental genes - myelination, axonal guidance, neuronal migration
  • ARC signalling - link neuronal activity → synaptic remodelling
  • Synaptic plasticity genes eg neuregulin — alters AMPA + NMDA receptor
  • VGCC — excitability + synaptic plasticity
  • DA metabolites + signalling eg COMT — alters DA release
  • Neuroinflammation genes
• Highest genetic risk for schizophrenia

  22q11 deletion — present in 30% patients
• Environmental/socio-developmental risk factors for schizophrenia

  • Family stress
  • Poor social interactions
  • Poor maternal nutrition
  • Infection/virus early age
  • Trauma at early age
  • Obstetric complications
• Prefrontal cortex (PFC)


  Involved in working memory + cognitive flexibility — 'Higher executive functions'
• Structural abnormalities in PFC in schizophrenia


  • Decreased dendritic field size of layer 5 pyramidal cells
  • Decreased spine density in pyramidal cells
• Hippocampus


  Centre for emotions, memory and ANS coordination
• Structural abnormalities in hippocampus in schizophrenia


  • Disorganised neuronal structure
  • Changes in hippocampal size + structure
• General structural abnormalities in schizophrenia

  • Enlargement of cerebral ventricles by 20%
  • Reduced gyrification + abnormal shaped folds
  • Decrease in grey matter volume
• Grey matter


  Neuronal soma, processes + synapses
• Changes in grey matter continue throughout disease course in schizophrenia
• Accelerated loss of grey matter in schizophrenia during adolescence
• PSD95 and synaptophysin reduced in post-mortem brains of schizophrenia patients
• Loss of synapses in schizophrenia is developmental not neurodegenerative
• Dopamine (DA)


  Evidence for DA dysfunction in schizophrenia
• Dopamine receptors


  • D1
  • D2, D3, D4
• Dopamine pathways


  • Mesolimbic
  • Mesocortical
  • Nigrostriatal
  • Tuberoinfundibular
• Mesolimbic dopamine pathway


  Hyperactive in schizophrenia — positive symptoms (?)
• Mesocortical dopamine pathway


  Hypoactive in schizophrenia — negative symptoms (?)
• Glutamine (Glu)


  Glu receptors - Ionotropic (iGluRs) and Metabotropic (mGluRs)
• NMDA receptor


  Hypofunction in schizophrenia
• Drugs that block NMDA receptors


  • Can induce psychosis eg ketamine + phencyclidine PCP
  • Acute psychosis + cognitive deficits in normal subjects
  • Exacerbates symptoms in schizophrenia patients
• Evidence for NMDA receptor hypofunction in schizophrenia


  • Antagonists induce schizophrenia-like behaviour
  • Expression of some subunits reduced in post-mortem tissue
  • Autoantibodies against NMDA causes clinical symptoms of schizophrenia
  • GRIN2A - NMDAR subunit-encoding gene associated with schizophrenia in GWAS
• Genes implicated in schizophrenia related to NMDA receptor

  • ErbB4 neuregulin receptor — colocalises with NDMA receptor — regulates kinetic properties
  • RGS4 inhibits signalling by mGluR5 Rs: mGluR5 localised near NMDA and potentiates currents
• Decreased NR1 (GluN1) subunit of the NDMA receptor in PFC in schizophrenia patients
• Genetic changes → changes in NMDA receptor function → synaptic plasticity — changes in learning + memory
• GABA


  GABAA receptors - 5 subunits round central pore
• Changes in GABAergic system in schizophrenia


  • Decreased mRNA conc for GAD67 — glutamic acid decarboxylase (synthesises GABA)
  • Decreased GABA membrane transporter 1 (GAT1) — responsible for GABA uptake
  • Changes in cortical interneurons — decreased parvalbumin in fast spiking interneurones in schizophrenia in hippocampus + PFC
• Perineuronal nets (PNN) and PV cells


  • PNN = condensed extracellular matrix forms a dense mesh around mainly PV cells
  • Stabilises synaptic connections + barrier to toxic substances so neuroprotective
  • PNN density increased in the PFC until early adulthood — significant decrease in layers 3 + 5 of PFC in schizophrenia but not bipolar disorder
• NMDA hypofunction


  Imbalance between GABAergic and glutaminergic neurotransmission → imbalance between excitation + inhibition (E-I imbalance)
• PFC pathways

  Human + rodent brains

  A) PFC

  B) NAc

  C) VTA

  D) TPP

  E) dorsolateral

  F) PFC

  G) NAc

  H) VTA

  I) TPP

  J) Medial

  
• Glutamatergic receptors

  NMDA-Rs, AMPA-Rs + Kainate Rs

  A) KA-R

  B) NMDA-R

  C) Presynaptic

  D) NMDA-R

  E) AMPA-R

  F) Kainate-R

  G) Postsynaptic

  H) GluN1

  I) GluN2A-D

  J) GluN3A+B

  K) GluA1-4

  L) GluK1

  M) GluK2

  N) GluK3

  O) GluK4

  P) GluK5

  Q) Ca2+

  R) Na+

  S) Na+

  T) glutamate

  U) Ionotropic