Lecture 8

• Drug targets for SCZ


  Refers to the molecules or pathways that are the focus of drug development for treating schizophrenia
• Link between GABA and NMDA


  • Decreased GAD67 and PV — both activity dependent
  • No total loss in PV cells
  • Spines — also change depending on input + activity
• Link between GABA, Glu + DA


  • Current antipsychotics all act on D2R target DA systems
  • Can manage +ve symptoms
• Preclinical models for SCZ


  Animal models, typically mice and rats, used to study schizophrenia
• Why do we need pre-clinical models?

  • Early changes — control time of disease course in rodent
  • Control the conditions — eliminate the confounds of human studies
  • Mechanisms — can do many studies not possible in humans
• Investigating key symptoms in SCZ


  • Locomotor activity — positive symptoms
  • Social interactions — negative symptoms
  • Cognitive performance — cognitive functions
• Investigating main patho-physiological changesin SCZ

  • Pyramidal cells - spines
  • PV cell morphology — PNNs
  • Beta + gamma oscillations
  • Neuroinflammation
• Modelling positive symptoms


  • Hyperactivity — increased locomotor activity — open field test
  • Increased stereotypic behaviours — rearing, obsessive grooming or eating
  • DA increase — amphetamine
  • PCP, ketamine + MK801 all increase activity
  • Open field is quick, easy and requires no animal training
• Modelling negative symptoms


  • Range of social interaction tests — animals natural behaviour to assess changes
  • Three chamber sociability test — easy, quick + requires no animal training
• Modelling cognitive symptoms


  • Sensory/motor deficits — PPI is impaired
  • Cognitive function — especially working memory — Odour span test, Spatial working memory in rodents
• Modelling executive function


  • Cognitive flexibility — attentional set shifting task
• Pathological changes in rodent models


  • Pyramidal cells spines
  • Changes in PNN
  • Changes in glial cell activation
  • Changes in PV interneurones
• NMDA receptor antagonist models


  • Diff treatment regimens — common is sub-chronic 7 days once or twice daily i.p. injection
  • Leave a few days for immediate drug effects to wash out
  • Can then do behavioural testing, record oscillations, or do immunohistochemistry
  • Now also do early neonatal injections to model early life injury
• Changes in PV+ interneurones


  • Reduced PV labelling after treatment with NMDA antagonist (eg PCP, ketamine) for 5 days
  • No assessment of cognitive function — changes can persist for weeks or months
  • Decreased PV labelling in rat pre-limbic region of the PFC following PCP treatment is reversed by clozapine but not haloperidol
  • Reduced dendritic asymmetric spines in the PFC following PCP is reversed by antipsychotic treatment
• MIA model of SCZ


  • Maternal immune inactivation — Inject poly I.C or LPS to mimic viral/bacterial infection
  • Maternal immune response — cytokines cross the placental barrier leading to inflammation in the offspring
  • Exhibit changes linked to SCZ — Abnormal sociability, Increased repetitive behaviours, Cognitive impairments, Decreased hippocampal volume, Early changes in microglia
• Changes in the PNNs on PV interneurones


  • In control mice — PNNs increase during development
  • MIA model of SCZ shows reduced PNNs + reduced proportion of PV cells within PNN when mice reach adulthood
  • Changes also varied in diff regions
  • Not linked to persistent immune response
• Rodent models of SCZ


  • Oscillations between hippocampus and PFC impaired
• Transgenic mouse that models the 22q11 deletion syndrome


  • Reduced firing of PV interneurons
  • Also reduced synchrony of activity
  • Restoring PV neuron function — Neuregulin peptide is neurotrophic factor, acts on ErbB4 Rs largely specific for PV interneurones, Modulates NMDA function
• C4 protein model


  • C4 protein involved in synaptic pruning
  • High expression of C4 — increased risk of SCZ
  • Increased C4 enhances microglia-mediated synaptic engulfment
  • Also increased = hypoconnectivity of PFC and reduced social interaction with the dam
  • Overexpression leads to PFC changes — Decreased excitatory transmission, Decreased spine number, Impaired inhibitory function, Impaired working memory
• Dual-hit (G-E) models


  • DISC1 K/O + MIA combined — add environment to genetic background
  • Decreased oscillations, especially beta, in the mPFC
  • Decreased dendritic length — restored with anti-inflammatory antibiotic minocycline — improve impaired cognition
• Advantages of models of SCZ


  • Models replicate many features of SCZ — some symptoms can be reversed by current treatments
  • Technology to manipulate specific cells — eg just PV interneurones — understand which cells involved
  • Good models to test new treatments
  • Also good to explore changes at different time points
• Disadvantages of models of SCZ


  • Slow — give a treatment for a long time
  • Need to assess right conc for drug treatment
  • ? When to treat and for how long — several experiments needed
  • Animal housing conditions — issue of reproducibility
  • Labour intensive + expensive
  • Many more cell types could play a role + other regions not discussed incl amygdala, thalamus and striatum
• Drug targets for SCZ

  A) Genetic changes

  B) Environmental effects

  C) Changes in development

  D) Neuroinflammation - microglia pruning

  E) PV

  F) Pyramidal cells

  G) E-I balance

  H) Beta/gamma

  I) long range synchrony

  J) cognition