Neurobiology of Schizophrenia

NEUROBIOLOGY OF
SCHIZOPHRENIA
Guide: Dr VS Pal Sir
Professor
Department of Psychiatry
MGMMC and MYH, Indore
By- Dr. Priyash Jain

Contents
■ Introduction
■ Neurotransmitters and Pathways
■ Genetics
■ Neurodevelopment
■ Neuroimaging
■ Immunology
INTRODUCTION
Introduction
■ In psychosis thought, behaviors, perception and feelings are disordered ; disorganized

and disconnected from reality.
■ Schizophrenia is the main psychotic illness.
■ Etiology of schizophrenia is unknown,
■ Genetic predisposition is clear and the role of environmental factors in the development
of schizophrenia is evident from the fact that monozygotic twins have approx 50%
concordance rates of schizophrenia.
Introduction
• Psychosis
– Delusions
– Hallucinations
– Disorganized speech
– Disorganized behaviour
– Gross distortions from reality
Introduction
• Symptom domains
– Positive
– Negative
– Cognitive
– Aggressive
– Affective
Introduction
• Positive Symptoms
– Delusions
– Hallucinations
– Distortions in language and communications
– Disorganized speech
– Disorganized behaviour
Introduction
• Negative Symptoms
– Alogia
– Affective blunting
– Asociality
– Anhedonia
– Avolition
Introduction
• Cognitive domains
– Poor concentration
– Poor attention
– Poor performance
– Poor learning
– Poor in
understanding
social cues
Introduction
• Aggressive Symptom domain

– Assaultiveness
– Verbally abusive behaviour
– Frank violence
Introduction
• Affective domain
– Inability to show expressions
– Inability to recognize emotions
– Depressed mood
– Anxiety
– Poor self esteem
– Guilt
– Suicidal thoughts
Localization of symptom domains
NEUROTRANSMITTE
RS
Neurotransmitters
• Dopamine
• Serotonin
• Glutamate
• GABA
• Acetylcholine
Dopamine
• Neurotransmitter
• Catecholamine
• Synthesized in brain and kidneys
Dopamine receptors- Location
D1 – Striatum, renal, mesentric vessels
D2 – Striatum, substantia niagra, Ventral
Tegmental Area, pituitary
D3– Nucleus Accumbens, hypothalamus
D4–Neocortex, midbrain, hippocampus,
medulla, heart & kidney
D5–Neocortex, midbrain, hippocampus,
medulla
Dopamine Pathways
• A- Nigrostriatal B- Mesolimbic C- Mesocortical

• D- Tuberoinfundibular E- Thalamic Dopamine pathway
Dopamine pathways
• Mesolimbic pathway
• Ventral tegmental area to
nucleus accumbens
• Motivation, pleasure and
reward
• Delusions and
hallucination
Mesolimbic Pathway
Mesocortical Pathway
Ventral tegmental area to
prefrontal cortex
• DLPFC
• cognition
• executive functions
• VMPFC
• Emotional
regulation
Mesocortical Pathway
• Low Dopamine
Nigrostriatal pathway
• Substantia nigra to basal
ganglia
• Extrapyramidal nervous
system
• Motor movements
• Deficiencies-
Bradykinesia
• Hyperactivity- Hyperkinetic
movement disorders
5HT – DA interaction at Nigrostriatal Pathway
Tuberoinfundibular pathway
• Arcuate Nucleus of
hypothalamus
• Anterior pituitary
• Inhibit prolactin
release
• Antipsychotic drugs-
increase prolactin
– Galactorrhea,
amenorrhea
Thalamic dopamine pathway
• Arise from multiple sites
– Periaqueductal gray matter
– Ventral mesencephalon
– Hypothalamic nuclei
– Lateral parabrachial nucleus
• Sleep and arousal mechanisms
• Gating info passing through thalamus to the
cortex and other brain areas
• Schizophrenia- Normal
Serotonin
• Serotonin receptors present in many brain
areas
• Cortical receptors- excitatory
• Enhances downstream glutamate release
Glutamate
• Excitatory
neurotransmitter
• Master switch of
brain
Glutamate Dysfunction
• Abnormalities in synapse formation during
neurodevelopment
• Genetic abnormalities
• Deficit in GABA
• Glutamate hyperactivity
• Increased Dopamine
• The major connections between these(PFC, hippocampus, and
thalamus) brain regions are glutamatergic, making this
neurotransmitter system central to the understanding of the
abnormal connectivity in schizophrenia.
GABA
■ GABA is synthesized from glutamate by glutamic

acid decarboxylase (GAD).
■ There are two isoforms of this enzyme, GAD65
and GAD67.
■ A consistent finding in schizophrenia is the
reduction in GAD67 levels in the PFC in
schizophrenia.
Acetyl choline
■ Cholinergic neurotransmission is integral to cognition and memory, functions that

are disrupted in schizophrenia
■ Schizophrenic patients have a much higher incidence of cigarette smoking.
■ Decreased levels of nicotinic and muscarinic receptors are reported in the
hippocampus, frontal cortex, thalamus, and striatum in schizophrenia.
■ Decreases in M1 and M4 receptors have been reported in the PFC and striatum in
schizophrenia.
■ There is also evidence of reduced expression of nicotinic receptor subunits α7 in the
frontal and reduced expression of α4β2 subtypes in the hippocampus in
schizophrenia.
■ These findings suggest cholinergic dysfunction in schizophrenia
GENETICS
Genetic
■ Schizophrenia is a highly heritable and polygenic illness.

■ Risk genes, including
– neuregulin (NRG),
– dystrobrevin-binding protein 1 (DTNBP1),
– disrupted in schizophrenia 1 (DISC1 and 2), and
– regulator of G protein-signaling-4 (RGS 4),
have been characterized in human postmortem tissue.
Risk for schizophrenia in the relatives of
schizophrenic patient
Epigenetic
■ Epigenetic regulation of chromatin can occur via several

mechanisms such as DNA methylation and posttranslational
modifications of histones.
■ There appear to be periods during development when epigenomic
changes take place in the human brain.
■ Maternal malnutrition, and viral infections, can lead toabnormal
epigenetic changes (hypermethylation) of DNA.
■ The epigenome might serve as a substrate that links
environmental exposures, genetic variants, and psychopathology.
NEURODEVELOPMEN
T
Neurodevelopment
■ PM studies in cortical tissue from schizophrenic

individuals found ectopic neurons and abnormal
cytoarchitecture in the PFC and entorhinal cortex.
■ These data shows impairment of neuronal migration of
these particular cells into the cortex during their critical
developmental period (2nd trimester).
■ Interpreted as evidence that schizophrenia is a
developmental disorder.
■ Synaptic elimination remains continue upto 3rd
decade of life before synaptic density stabilizes at
adult levels.
■ Some studies shows schizophrenia as a defect of
excessive pruning during adolescence.
Synapse Formation
Myelination abnormalities
■ This theory originated from structural imaging studies, who found that
white matter regions, in addition to grey matter regions, showed
volumetric reductions in patients with schizophrenia .
■ Gene expression studies have shown abnormalities in myelination and
oligodendrocytes in post-mortem brains of schizophrenia patients.
■ Furthermore, oligodendrocyte numbers appear to be reduced in several
post-mortem studies.
■ Myelination abnormalities could be originate from impaired maturation
of oligodendrocyte precursor cells, as these have been found to be intact
in schizophrenia brains.
NEUROIMAGING
Structural Abnormalities
• Ventricles- Increased
size of lateral ventricles
• Reduced cortical gray
volume
• Progressive or static
• Reduced symmetry
– Neurodevelopmental
Prefrontal Cortex
• Anatomical Abnormalities
• Functional deficits on neuroimaging
• Symptoms of Schizophrenia mimics –
frontal lobotomies and frontal lobe
syndrome
LIMBIC SYSTEM
• PM findings and MRI -
decrease in the size of
the limbic system
including the amygdala,
the hippocampus, and
the parahippocampal
gyrus
• Hippocampus is small,
functionally abnormal
and has disorganised
neurons
THALAMU
•
S
Volume shrinkage
• Neuronal loss of
medial dorsal nuclei
• Number reduced to
30-45%
Basal ganglia and Cerebellum
• Involved in motor control of movements

• Schizophrenia causes odd movements, gait, facial
grimacing
• Cell loss and shrinkage in volume
• Increase in number of D2 receptors
Neural Circuits
• Early developmental lesions of
dopaminergic tracts
• Disturbances in connectivity in different
brain regions
• White matter fibre tracts
IMMUNOLOGY
Immune system abnormalities
■ Abnormal immune system development may help explain roles of environmental effect
such as prenatal hazards, post-pubertal onset, stress, climate, and infections, in addition
to genetic effects.
■ Supported by findings of high levels of immune markers in the blood of schizophrenia
patients.
■ High levels of immune markers have also been associated with having more severe
psychotic symptoms.
■ One study discovered that single-nucleotide polymorphisms (SNP) significantly
associated with schizophrenia were located in the major histocompatibility
complex region of the genome.
Conclusion
■ There is neither a single brain region nor a single neurochemical

alteration but several, which have been associated with schizophrenia.
■ The PFC, hippocampus, and thalamus are the regions most often
implicated, perhaps in part because these are the regions most studied.
■ At the cellular level, reduced gray matter volumes, reduced size of
neurons but without cell loss, and reduced dendritic arborization and
spines are the main observations seen in schizophrenia.
■ White matter changes also contribute to connectivity deficits between
brain regions implicated in schizophrenia.
Reference
■ Kaplan and Sadock's Comprehensive Textbook of Psychiatry, 10th edition

■ Stahl’s Essential Psychopharmacology 4th edition

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NEUROBIOLOGY OF

By- Dr. Priyash Jain

■ In psychosis thought, behaviors, perception and feelings are disordered ; disorganized

• Aggressive Symptom domain

• A- Nigrostriatal B- Mesolimbic C- Mesocortical

■ GABA is synthesized from glutamate by glutamic

■ Cholinergic neurotransmission is integral to cognition and memory, functions that

■ Schizophrenia is a highly heritable and polygenic illness.

■ Epigenetic regulation of chromatin can occur via several

■ PM studies in cortical tissue from schizophrenic

• Involved in motor control of movements

■ There is neither a single brain region nor a single neurochemical

■ Kaplan and Sadock's Comprehensive Textbook of Psychiatry, 10th edition

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