Schizophrenia is a psychotic disorder involving disordered thoughts and perceptions. The neurobiology of schizophrenia involves abnormalities in several brain regions and neurotransmitter systems. Genetic and environmental factors contribute to disruptions in neurodevelopment that impact dopamine, glutamate, and other neurotransmitter pathways. Structural brain imaging shows enlarged ventricles and reduced volumes in the prefrontal cortex and limbic regions. Immune system abnormalities may also play a role in schizophrenia pathogenesis. Overall, schizophrenia has diverse neurobiological underpinnings rather than a single brain or chemical abnormality.

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

2. Contents
■ Introduction
■ Neurotransmitters and Pathways
■ Genetics
■ Neurodevelopment
■ Neuroimaging
■ Immunology

3. INTRODUCTION

4. 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.

5. • Psychosis
– Delusions
– Hallucinations
– Disorganized speech
– Disorganized behaviour
– Gross distortions from reality
Introduction

6. • Symptom domains
– Positive
– Negative
– Cognitive
– Aggressive
– Affective
Introduction

8. • Positive Symptoms
– Delusions
– Hallucinations
– Distortions in language and communications
– Disorganized speech
– Disorganized behaviour
Introduction

9. • Negative Symptoms
– Alogia
– Affective blunting
– Asociality
– Anhedonia
– Avolition
Introduction

10. • Cognitive domains
– Poor concentration
– Poor attention
– Poor performance
– Poor learning
– Poor in understanding social cues
Introduction

11. • Aggressive Symptom domain
– Assaultiveness
– Verbally abusive behaviour
– Frank violence
Introduction

12. • Affective domain
– Inability to show expressions
– Inability to recognize emotions
– Depressed mood
– Anxiety
– Poor self esteem
– Guilt
– Suicidal thoughts
Introduction

13. Localization of symptom domains

14. NEUROTRANSMITTERS

15. Neurotransmitters
• Dopamine
• Serotonin
• Glutamate
• GABA
• Acetylcholine

16. Dopamine
• Neurotransmitter
• Catecholamine
• Synthesized in brain and kidneys

17. 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

18. Dopamine
Pathways
• A- Nigrostriatal B- Mesolimbic C- Mesocortical
• D- Tuberoinfundibular E- Thalamic Dopamine

19. Dopamine pathways
• Mesolimbic pathway
• Ventral tegmental area
to nucleus accumbens
• Motivation, pleasure
and reward
• Delusions and
hallucination

20. Mesolimbic Pathway

21. Mesocortical Pathway
Ventral tegmental area to
prefrontal cortex
• DLPFC
• cognition
• executive functions
• VMPFC
• Emotionalregulation

22. Mesocortical
Pathway
• Low Dopamine

23. Nigrostriatal pathway
• Substantia nigra to basal
ganglia
• Extrapyramidal nervous
system
• Motor movements
• Deficiencies-
Bradykinesia
• Hyperactivity- Hyperkinetic
movement disorders

25. 5HT – DA interaction atNigrostriatal Pathway

26. Tuberoinfundibular pathway
• Arcuate Nucleus of
hypothalamus
• Anterior pituitary
• Inhibit prolactin
release
• Antipsychotic drugs-
increase prolactin
– Galactorrhea,
amenorrhea

28. 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

29. Serotonin
• Serotonin receptors present in many brain
areas
• Cortical receptors- excitatory
• Enhances downstream glutamate release

30. Glutamate
• Excitatory
neurotransmitter
• Master switch of brain

32. 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.

33. 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.

34. 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

35. GENETICS

36. 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.

37. Risk for schizophrenia in the relatives of
schizophrenic patient

38. 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.

39. NEURODEVELOPMENT

40. 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.

41. ■ 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.

42. Synapse Formation

43. 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.

44. NEUROIMAGING

45. StructuralAbnormalities
• Ventricles- Increased
size of lateral
ventricles
• Reduced cortical gray
volume
• Progressive or static
• Reduced symmetry
– Neurodevelopmental

46. PrefrontalCortex
• Anatomical Abnormalities
• Functional deficits on neuroimaging
• Symptoms of Schizophrenia mimics –
frontal lobotomies and frontal lobe
syndrome

47. 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

48. THALAMUS
• Volume shrinkage
• Neuronal loss of
medial dorsal nuclei
• Number reduced to
30-45%

49. 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

50. NeuralCircuits
• Early developmental lesions of
dopaminergic tracts
• Disturbances in connectivity in different
brain regions
• White matter fibre tracts

51. IMMUNOLOGY

52. 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.

53. 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.

54. Reference
■ Kaplan and Sadock's ComprehensiveTextbook of Psychiatry, 10th edition
■ Stahl’s Essential Psychopharmacology 4th edition