Lecture 7

• 1. E-I imbalance


  • Drives some DA changes
• New drug targets


  1. Increase PVI drive

  2. Increase NMDAR function through glycine site

  3. Kv3.1 modulators

  4. Increase postsynaptic GABA actions

  5. a5-GABAA PAMs

  6. Decrease impact of Pyr hyperactivity

  7. mGluR2/3 agonists
• Neuroinflammation


  • Microglia + astrocytes activate — change shape
  • Microglia release pro-inflammatory cytokines including IL-6, IL-10 and TNF-alpha
  • Acute — can be good
  • Chronic — bad
• High serum inflammatory markers


  Grey matter loss in the mPFC
• Activated microglia


  Can prune/engulf synapses — reduced synapse number
• MHC


  • GWAS identified on chromosome 6 — C4 gene
  • MHC locus highest association to SCZ
  • C4 involved in synaptic pruning
  • High C4 expression associated with increased SCZ risk
  • Increased C4 enhances microglia-mediated synaptic engulfment — inflammation may impact synapse numbers
• Traffic-related air pollution


  Alters brain development + increase risk of SCZ — unsure direct link
• Neuroinflammation not unique to SCZ
• Cognitive abnormalities in SCZ


  • Disruptions in information processing/sensory perception
  • Deficits in attention, working memory + behavioural flexibility
  • Sensory gating deficits
• Sensory gating deficits


  • Reduced P50 correlated with attention and reflects deficits in inhibition — sensory overload
  • Top down + bottom up processing — SCZ cant link info
• Working memory (WM)


  Ability to transiently maintain and manipulate a limited amount of information to guide thought and behaviour
• Tests for WM


  • Match-to-sample task
  • N-Back task
• WM in SCZ


  • Decreased fMRI signal in DLPFC correlated with poor performance
  • Specific deficit seen in SCZ
  • Leads to other deficits in other cognitive functions
  • More extensive network for memory is seen in controls compared to SCZ patients
• Tests for executive functions


  • Wisconsin card sorting tasks
  • Stroop test
• Disconnection hypothesis


  SCZ show disrupted coupling between brain regions due to faulty wiring + impairments in synaptic transmission + plasticity
• SCZ show decreased functional connectivity between brain regions
• Long range synchrony


  Processing of different memories, perceptions and emotions across distant brain regions (>1cm — eg across hemispheres + cortical regions)
• EEG


  • Electroencephalogram (EEG)
  • Electrodes attached to the head - traces correspond to recording of one electrode
  • Different patterns of activity can be detected
• EEG signals of cognitive relevance


  • Delta = 0.5-4 Hz — during sleep
  • Theta = 3-7 Hz
  • Alpha = 9-11 Hz
  • Beta = 15-30 Hz
  • Gamma = 30-60 Hz — awake state
  • High gamma = >60 — >1 freq at a time
  • Ultrafast = >100 Hz — diff cognitive functions
• Gamma + theta involved in memory functions in PFC + hippocampus
• Beta + gamma also linked to sensory processing
• Gamma oscillations


  • Involved in complex excitatory + inhibitory interactions
  • Changes → imbalances in the system
  • Patients have reduced long range synchrony — consistent with disconnection hypothesis
• Gamma activity in the delay period


  Reduced in SCZ patients — no gamma = no memory
• Decreased long range synchrony at 20-30 Hz


  In response to Mooney faces in SCZ
• Modulating gamma oscillations


  Rhythmic visual and auditory stimulation of human participant with simultaneous EEG recording
• Hallucinations


  • Associated with increased gamma in sensory areas
  • Increased long range synchrony
  • Could be due to abnormal plasticity
• E-I imbalance causes

  A) PVI dysfunction

  B) Positive symptoms

  C) Cognitive deficits

  D) Negative symptoms

  E) Pyr output

  F) mPFC

  G) vHipp

  H) VP

  I) VTA

  J) Ventral striatum

  K) Sensory striatum

  L) Associative striatum

  M) BLA