NEUR 3502

Neurodevelopmental
Determinants of Mental Health
Professor: Patrice Smith, Ph.D.
Department of Neuroscience, Faculty of
Science, Carleton University

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 Class Objectives
• Schizophrenia (SCH)
– Neurodevelopmental models of SCH

– Genetics and environmental contributors

– Dopamine hypothesis

– Hypofrontality

– Potential treatment options

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 Schizophrenia
• Poorly understood neurological condition
characterized by
– Delusions
– Hallucinations
– Disorganized speech
– Alterations in perception, cognition, planning
and motivation
• Age of onset: usually early adulthood
– Coincide with maturation of prefrontal cortex

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 Schizophrenia
• Cause is not known
– Research dedicated to finding a cause
– Genetic susceptibility factors ...
– Potential environmental contribution ...
• Several hypotheses exist
– Neurodevelopmental hypothesis
– Dopamine hypothesis
– Hypofrontality hypothesis
– Glutamate hypothesis
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 Models of schizophrenia
• Environmental models
– Schizophrenia evoked by increased social
demands during early adulthood …
• Genetic models
– Suggest potential genetic cause of schizophrenia
– Genetic susceptibility to environmental stimulants
…
• Neurodevelopmental models
– Normal brain development is disrupted
– Symptoms seen during specific maturation stages,
usually in late adolescence or early adulthood
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 Potential Genetic Contribution
• Heterogeneity model
– Separate distinct diseases, each inherited
based on specific gene mutation
• Monogenic model
– Dominant single-gene mutation resulting in
highly variable phenotypic expression
• Polygenic model
– Outcome caused by multiple gene mutations
• Combinatorial model
– Results from complex interactions between
genetic susceptibility and environment
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Genetics in the etiology of SCH

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 Dopamine Hypothesis
• Specific dopaminergic pathways (D2 receptor) are
overactive in schizophrenia
• Most established hypothesis of schizophrenia (Van
Rossum, 1967)
• Supported by clinical use/effectiveness of
dopamine D2 receptor antagonists in the treatment
of some SCH symptoms
• Supported by psychosis-inducing effects of D2-
receptor agonists (Liebermann et al., 1987)
• Revised dopamine hypothesis has been proposed
…
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 Neurodevelopmental
Hypothesis of Schizophrenia

Brain abnormality present at or

shortly after birth is “unmasked”
as a result of normal maturation
events that occur in late
adolescence and early adulthood.
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 Stages of Neurodevelopment
• Neurogenesis: birth/generation of neurons
• Migration: neurons move from area of birth to
dedicated positions in brain
• Growth: axons grow toward targets
Synaptogenesis: Synapse formation
• Synaptic pruning: loss of some synapses,
strengthening of others
• Neuronal death: neuronal loss (apoptosis …)
• Myelination: oligodendrocytes myelinate neurons …
• activity-dependent changes …

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 Timing of synaptic pruning

Emergence of SCH symptoms correlate with stage of

development occupied by significant synaptic pruning
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 SCH: disorder of the synapse
• Glutamate (GLU) synapse
malfunction?
– GLU: major excitatory
neurotransmitter
– Abnormal function at
the GLU synapse
– Effect on
neurotransmission and
plasticity
– Several gene mutations
implicated
• DISC1 …
http://www.nature.com/mp/journal/v12/n10/fig_tab/4002062f1.html 12
 SCH susceptibility genes …
• DISC-1 (disrupted in schizophrenia-1)
• DTNBP1 (Dysbindin - dystrobrevin-binding
protein 1 - gene)
• NRG1 (neuregulin-1)
• RGS4 (regulator of G protein signaling 4)
• COMT (catechol-O-methyltransferase)
• PDE4B (phosphodiesterase 4B)
• …
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 DISC-1 (Disrupted in SCH -1)
• Functions are not yet clearly defined
• Role in forebrain development
• Highly expressed in areas where
neurogenesis occurs …
• Many molecular interacting proteins;
potential role in regulating:
– Neuroplasticity
– Axon growth
– Neuronal migration
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 DISC1 function in `neural connectivity
during development?

Spine number (possible synaptic sites) during development

Penzes et al., Nat Neurosci 2011 15

 Schizophrenia: a disorder of connectivity
• Disorder of cortical connectivity
– Neuroimaging techniques: diffusion tensor
imaging (DTI) and fMRI
– Structural or functional analyses
• Frontal lobe
• Schizophrenia typically starts in late adolescence
– remodeling of cortical connections during this
period is thought to be critical
– Distinct neurodevelopmental stages …

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 Neurodevelopmental Stages of Schizophrenia

Insel, T. R. Arch Gen Psychiatry 2009;66:128-133.

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Copyright restrictions may apply.
 SCH stages and gray matter development

PFC inhibitory
synapses

PFC excitatory
synapses

Deficient
myelination

Excessive
Excitatory
pruning

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http://www.nature.com/nature/journal/v468/n7321/fig_tab/nature09552_F1.html
 Neurobiological Correlates
• Imaging studies show
– Decreased brain volume (white matter)
• frontal lobe, cerebellum and limbic structures
– Alterations in neurotransmitters (dopamine,
serotonin, and glutamate)
• Dysregulation Hypothesis:
• unstable neurotransmission
• Neurodevelopment basis:
• several abnormal brain structures/circuits
interfere with function
–prefrontal cortex and hippocampus
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 Brain pathology in SCH

N Eng J Med. 1990. “Normal” Twin Twin with SCH

• Lateral Ventricle enlarged

• Reduced brain volume (particularly gray matter)

• Abnormal/reduced neuronal complexity

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 Neurodevelopmental - dopamine
hypothesis
• Abnormal neurodevelopment results in excessive
dopamine activity in the limbic system and reduced
activation within the prefrontal cortex

HYPOFRONTALITY:
• Lower frontal lobe activity
• Reduced axon density in the prefrontal cortex
• Reduced dopamine activity in the prefrontal cortex
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 Summary …

Graham et al, Eukaryon, Vol. 12, March 2016 22

Neural Compensation in SCH

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 Stress and SCH
• Correlation between experiencing stressful
event and SCH symptoms
• Stressor exposure associated with
worsening of SCH symptoms
• Stress response mechanisms appear to
be abnormal in some individuals …
• Mechanisms around the impact of stress
on SCH are not clearly defined …

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 Intervention
• Combination of behavioural and pharmacotherapy
• Pharmacotherapy:
– Typical antipsychotics
• Clozapine (atypical antipsychotic)
– reserved for patients with treatment resilient
illness; severe side effects, such as
agranulocytosis and seizures
• Without medication, schizophrenics relapse at a
rate of 60-70 % within the first year of diagnosis

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 Take home message …
• Developmental theories of SCH suggest that
abnormality in brain development
– Major predisposition to SCH
• Causal event may occur during development
• Symptoms typically emerge in late adolescence or
early adulthood
– Correlated with specific neurodevelopmental
stages
• Several neurotransmitter systems involved
• Finding a unifying theory to explain all the signs
and symptoms of SCH is very challenging …
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• Midterm update …

Next class … Disorders of

mood…

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