Theories of sz

AN update about the neurobiology of Sz.

1. Theories of
Schizophrenia
Dr Parth Goyal

2. Learning Objectives
•To learn about the neurobiological basis of
schizophrenia
•To understand the strengths and limitations of
each of these theories
•To understand Prodrome: as a window to the
brain before the onset of full blown psychosis

3. Prodrome of Sz
•Approx 80-90% of patients with schizophrenia have a prodrome, which is
characterised by emergence of attenuated or sub threshold symptoms which
lie of the continuum of with positive symptoms.
•Most commonly:
•a) Perplexity or Confusion
•b) Over Valued ideas
•c) Hearing indistinct voices
•d) Guardedness
•Such patients are known as “Prodromal”of “Clinically High Risk” sample.
•This phase typically lasts for 1 year.

4. Importance of Prodrome
•Prodrome is a potent predictor of
psychosis
•Most of the conversion from CHR
to psychosis spectrum occurs in
the first year.
•Patients in prodrome provide a
unique opportunity to study the
baseline brain structures, before
full blown illness develops.
•By virtue of their temporal priority
it may represent the pathway
ultimately leading to psychosis.

5. Biological Theories
•There are three main theories proposed to
explain the development of Sz
•a) The Dopamine Hypothesis
•b) The Excitation-Inhibition Model (Glutamate
Hypothesis, also k/a NMDA hypo function
Hypothesis)
•c) The Neurodevelopmental Model.

6. Limitations of Research
Studies
•No direct brain examination is possible in human
subjects.
•In order to better understand the neurobiology, the
sample must be studied before the onset of psychosis
and followed up till end of life.
•The effects of antipsychotics and other medications
on the brain is difficult to control for.
•SZ in itself is a heterogeneous, chronic condition with
a variable course.

7. Dopamine Hypothesis
•For the longest time, the central theory to explain
Sz.
•Based on the following findings
•a) Typical antipsychotics were found to be
effective in treating psychotic states
•b) Dopamine stimulating drugs e.g.
amphetamines are known to induce short lived
psychotic states.

8. Dopamine Pathways
•1) Mesolimbic Pathway
•2) Mesocortical Pathway
•3) Nigrostriatal Pathway
•4) Tuberoinfundibular Pathway
•5) Thalamic Pathway

9. Mesolimbic Pathway and
Psychosis
•DA released from VTA to the Nucleus Accumbens
in the Limbic System
•Important role in emotional behaviours including
motivation, pleasure and rewards.
•Hyperactivity in this pathways is considered to be
responsible for the positive symptoms of Sz.
•Hyperactivity of this pathway may also play a role
in aggressive and hostile symptoms of Sz.

10. Limitations of this model
•What causes the increased release of DA from
the VTA to the NA is currently not known.
•Newer models have suggested the role of
GLUTAMATE dysfunction.

13. Mesocortical DA Pathway
•DA from VTA to Prefrontal Cortex (PFC)
•Two parts of the PFC; Ventromedial PFC, Dorsolateral
PFC
•The negative and cognitive symptoms of SZ, can be
attributed to a DEFICIT of DA projections from the VTA
to the PFC
•The affective and cognitive symptoms of SZ can be
attributed to the DEFICIT of DA projections from the
PFC to the VTA.

16. Limitations of this model
•What causes the increased release of DA from
the VTA to the NA is currently not known.
•Newer models have suggested the role of
GLUTAMATE dysfunction.

18. Glutamate Hypothesis
•The glutamate hypothesis is considered to be the
leading theory for explaining schizophrenia
•Glutamate is an excitatory neurotransmitter in the
brain
•It is considered to be the “Master Switch” as it can
virtually switch on all the neural circuits in the brain.
•Glutamate is also very important for normal synapse
formation and maturation of the growing brain.

19. Glutamate
•Glutamate is an amino acid and it is utilised in
the brain as an excitatory neurotransmitter.
•When used as an NT it is synthesised from the
Glial cells in the brain.
•Its action is terminated by uptake into the nearby
glial cell by an transporter protein.

20. Co-Transmitters in
Glutamatergic Transmission
•Glutamate can act on post synaptic receptors
especially NMDA receptors only in the presence
of certain co-transmitters
•They include Glycine and D-Serine.
•Both these NT’s are synthesised in the brain and
are available at the glutamate synapse for its
action.

21. Glutamate Receptors
•There are two main types of Glutamate receptors
based on their molecular actions.
•a) Metabotropic Glutamate Receptors: There are
8 subunits of the same. GluT 1-8. These are G-
protein coupled receptors.
•b) Inotropic Receptors: NMDA/ AMPA/ Kinate
receptors. These are ion gated receptors.

22. Metabotropic Glutamate
Receptors
•There are three main classes of metabotropic glutamate receptors:
•Group 1: Mainly located post synaptically and play an important
role in glutamate induced plasticity and other excitatory
neurotransmission.
•They affect neuroplasticity and gene expression via the modulation
of the signal transduction pathways.
•Group 2 & 3: Located presynaptically and predominantly work as
auto receptors, regulating glutamate release at synapses.
•They regulate the pre synaptic activity by modulating the activity of
K
+
and Ca
+2
channels and by interfering with the downstream
release of Ca.

23. Presynaptic Auto receptors (mGluR 2,3)

24. Inotropic Glutamate
Receptors
•They are located post-synaptically and include:
•NMDA, AMPA, Kinate family of receptors.

26. Pharmacology of Glutamate Receptors

27. Physiologic Roles of
Glutamate
•There are 3 main physiologic functions of
Glutamate:
•a) Synapse formation and Synapse Maturation
•b) Synaptic Plasticity
•c) Neurotoxicity.

28. Role of Glu in Brain
Development
•Glutamate is very important for synapse
development early on in the developing brain.
•Glutamate by the process described below is
responsible for synaptic development and
proliferation.
•In people who has deficient glutamate or NMDA
receptors, aberrant growth patterns are noticed,
and this can lead to dysconnectivity in brain
circuits.

30. Role of Glu in Synaptic
Plasticity
•The ability of neurons to adapt to the changes in the
environmental factors is known as synaptic plasticity.
•Plasticity can be of two types: Short lived and long
lived.
•Short lived include depolarisation of membranes and
long lived includes altered gene and protein synthesis
that affects the properties and shapes of neurons
•This property is mediated by glutamate via its action on
the AMPA/ NMDA receptors located post synaptically.

31. Process of synaptic plasticity
•NMDA receptors under normal resting conditions are blocked by
Mg
+2
ions.
•Ca
+2
influx is required for the process of Long term potentiation to
occur.
•In order for this process to occur to 3 events should occur
simultaneously:
•1) Binding of Glutamate to NMDA receptors
•2) Binding of Glycine/ D-serine to their site on the NMDA receptor
•3) Simultaneous depolarisation of the NMDA receptor.

32. Contd.
•The functional consequences of Ca
+2
influx
include
•a) increased sensitivity to glutamate
•b) promotions of neuritic growth, cell adhesion
and cellular interactions.
•All these represent the structural substrate for
neuroplasticity.

33. Differential actions of AMPA and NMDA Receptors.

34. Role of Ca
+2
in mediating changes at a molecular level.

35. Role in Neurotoxicity
•Excessive stimulation of glutamate can compromise the neuronal viability by
impeding the structural and functional integrity. This is known as excitotoxicity.
•Mechanisms by which glutamate can induce excitotoxicity:
•a) Excessive stimulation by glutamate can lead to increased accumulation of

Na and Cl into the cell, causing the cell to rupture.
•b) A Ca
+2
dependent delayed apoptotic death can also be initiated, due to
intra cellular elevations of Ca
+2
, which causes mitochondrial damage, drop in
ATP levels and build up of ROS.
•Also excessive intracellular calcium can cause an activation of the
Arachadnoic acid pathway which causes the formation of free radicals, which
in turn damage the cell by attacking proteins, lipids and mediating lipid per
oxidation of cell membranes.

36. Glutamate mediated Excitotoxicity.

37. Glutamate and
Schizophrenia

40. NMDA Receptor
Hypofunction
•This is the leading hypothesis to explain the symptoms of
Sz.
•This hypothesis is devised from the following
observations:
•a) NMDA antagonists like PCP and Ketamine produce
psychotic symptoms in normal populations and
exacerbate the psychotic symptoms in schizophrenia
patients.
•b) PCP in normal individuals mimics positive as well as
negative and cognitive symptoms.

41. Under Normal Conditions
•The GABA neurons are identified in the PFC as calcium
binding protein containing known as Parvalbumin.
•The GABA neurons are innervated by glutamate through
its action on the NMDA receptor.
•This leads to release of GABA at the synapse.
•The GABA neurons further synapse with Glutamatergic
neurons.
•The release of GABA inhibits further release of Glutamate
into the system.

43. Hypoactive NMDA
Receptors.
•Deficient functioning of the NMDA receptors at the GABA synapses
due to a variety of developmental factors can lead to disturbances
in glutamatergic transmission across the cortex.
•These parvalbumin containing GABA neurons contain a hypo
functional NMDA receptor.
•This hypo functional NMDA receptors leads to inadequate
stimulation of the GABA neuron, which in turn causes decreased
release of GABA.
•This in turn causes a deficient inhibition of Glutamate neuron, which
in turn increases the amount of glutamate available in the CNS.
•This is hypothetically responsible for Sz symptoms.

45. Linking NMDA Hypofunction with Dopamine
Hypothesis

46. NMDA hypothesis and
Positive Symptoms
•Hypo functioning NMDA receptors in the PFC lead
to decrease in GABA levels in the PFC, which
causes decreased inhibition of the Glutamatergic
neurons, leading to increased glutamate levels in
the PFC.
•This increase in the glutamate levels in the PFC,
lead to increased stimulation of the VTA via its
direct projections, which in turn leads to increased
DA release in the striatum, causing positive
symptoms of Sz.

47. Second Pathway for Positive
Symptoms
•Under normal conditions, the action of glutamate on the
NMDA receptors in the hippocampus, causes a release
of GABA on the GABAergic neurons located in the NA.
•This causes an inhibition of glutamate release from the
NA (normal amounts of glutamate is released, not
excessive amounts)
•This glutamate acts on NMDA receptors of GABAergic
neurons of the Globus Pallidus, causing GABA release,
which in turns acts on the GABAergic neurons of the
VTA, inhibiting excessive DA release in the stratum.

48. Positive Symptoms contd..
•Hypothetically hypo functional NMDA receptors
are also located on the GABA neurons in the
hippocampus.
•This leads to decreased GABA release, causing
an increase in Glutamate release in the NA, which
causes increased GABA release in the GP (more
than normal amounts), which further inhibits the
inhibitory projections into the VTA, causing an
increased DA release into the striatum, causing
the positive symptoms.

49. NMDA hypothesis and
Negative Symptoms
•NMDA receptors stimulation in the PFC, releases
glutamate, which by an indirect cortico-cortical
pathway innverate a GABAergic neuron.
•This innervation causes a release of GABA into
the VTA, which in turn inhibits the mess cortical
projections, thus inhibiting the DA release into
the cortex.

50. Abnormality
•Hypoactive NMDA receptors cause deficient
inhibition of Glutamate, leading to increased
glutamate concentrations in the PFC, which
causes enhanced stimulation of the GABA
interneuron.
•This increased GABA acts on the DA neurons in
the VTA, inhibiting them.
•This leads to decrease in the DA released into the
PFC, causing the negative symptoms of Sz.

51. NMDA Hypothesis and
Symptoms of Sz
•Prediction error: Neural signals which indicate
when a particular observation appears
inconsistent with prediction, based on an
internal schema or model explaining the
meaning of such observation given prior
learning.

52. Contd..
•The NMDA hypothesis attempts to explain the
formation of delusion by interrupting these prediction
error signals that mediate between belief and
experience.
•In the prodromal phase, the network of previously
learned associations that guide reality construction
and interpretation are challenged by new experiences
inconsistent with this predictive coding.
•This leads to perplexity and confusion. this is caused
by a reduction in NMDA receptors.

53. Contd.
•As there is a further decrease in NMDA receptors, the
effects of previously learned information in interpreting new
information gets loosened, and predictive error signalling
drops off.
•This leads to new interpretations aka new reality
construction.
•The fixity of the delusional beliefs can be explained by the
paradoxical strengthening of these new associations
during the process of memory consolidation due to
absence of prediction error signalling occurring due to lack
of NMDA receptors.

54. Neurodevelopmental
Hypothesis of Sz
•Nature v/s Nurture
•According to this theory Sz is not caused by any
one particular abnormality.
•It occurs as an interplay between various factors
both biological (genes) and environmental
(stressors)
•Brain dysconnectivity is considered to be a
primary mechanism in the genesis of Sz

56. Key Genes
•The main genes involved in the neurobiology include:
•1) Dysbindin: Formation of synaptic structures and
regulation of activity of vGLuT.
•2) Neuregulin: Neuronal migration, genesis of glial
cells, myelination of neurons.
•3) DISC1: Neurogenesis, neuronal migration and
dendritic organisation, transport of synaptic vesicles
into presynaptic glutamate terminals and regulates
cAMP signalling, important for mGLu receptors.

57. Abnormal Gene Expressions
•Brain dysconnectivity, due to an interplay between the
various genetic factors as mentioned above leads to:
•a) deficits in dendritic spines
•b) disrupted myelination
•c) aggressive pruning of neurons because of the
presence of hypo functional receptors and aberrant
growth patterns.
•d) abnormal growth trajectories of various axons leading
to disconnection

61. Linking 2 models
•Primarily the reduction in synapses and dendritic outgrowths
as noted in PM studies are localised to the gluatamatergic
cells.
•Thus NMDA receptor dependent processes including long
term potentiation seems to be compromised during this
normal stage of development.
• Thus the synapses which do not undergo LTP, remain
vulnerable and are more susceptible to pruning during the
adolescent years of life.
•The more the synapses that get pruned, the greater the
dysconnectivity in the brain.
•This provides the evidence to link the neurodevelopmental
model with the glutamate hypothesis of schizophrenia.

62. Neurodevelopmental Hypothesis
and Symptoms of Sz
•Source Memory: Memory for the context of learning with particular
reference to whether the item, event or experience was real or
imagined and was by which agent (self or some one else)
•Salience: Incentive value of a stimuli as encoded neurally and as
expressed by its effects on attention and other cognitive processes.
•Areas of the brain and their function:
•a) Lateral PFC: Role in memory retrieval
•b) Medical PFC: Role in performed action
•c) Paracongualte Gyrus: Role in reality monitoring task.

63. Source Memory Deficits
•Beliefs as well as episodic memory include source
monitoring.
•Thus the hypothesis is that delusions can emerge as a
consequence of progressive connectivity loss in areas
involved in source monitoring during memory
encoding and retrieval.
•What it means is that disruption of source monitoring
during learning and memory may lay the groundwork
for subsequent development of disruptions in belief
evaluation.

64. Clinical Picture in Prodrome
and Clinical States.
•Confusion and perplexity: During prodrome, deficits in
source monitoring can explain the confusion about:
•a) Real v/s Imaginary
•b) Changes in the interpretations of events or experiences
such that familiar begins to feel strange, ominous,
threatening or having a special meaning.
•The fixity of the delusion can also be explained as a function
of source monitoring deficit, where after a faulty explanation
develops, the skepticism for this explanation can erode,as
the original memory is subject to source confusion.

65. Internal Source Monitoring
Deficits.
•Hallucinations can also be explained in the similar
way, where deficits in internal source monitoring
involving subvocal speech and internally
generated ideation can lead to confusion in the
individual.
•The evidence regarding this is primarily derived
from brain imaging studies which include thinning
of the cortical regions involving both the areas
required for internal source monitoring and
auditory verbal processing.

66. Synaptic Pruning

68. Linking the 2 models.

69. Inflammation and Immunity
in Sz
•Complex immune brain interaction can affect normal neural
development and can have causal and therapeutic implication
for a number of psychiatric illness including Sz.
•The immune system and the brain share some common
features:
•a) Highly complex systems
•b) Possess memory
•c) develop through interaction with the external environment
•d) able to distinguish self from non self.

70. Immune and infection link to
psychosis
•A possible association between Sz and immune
system was postulated a century ago.
•A pre natal maternal infection with influenza, HSV
-II, CMV and toxoplasmosis Gondii have been
associated with Sz in adults.
•Reduced concentration of acute phase proteins in
neonates might increase the risk of adult
psychosis by increasing the susceptibility to
infections.

71. Immunity and the Brain
•The immune cells of the CNS are the microglia which are present
in a number approximately equal to the neurons in the brain
•In response to the systemic inflammation, the microglia also
release cytokines in the brain, which can have an impact on:
•a) NT’s
•b) Synaptic Plasticity
•c) Cortisol concentrations
•All of this can lead to changes in mood, cognition and behaviour.

72. Effect on neurodevelopment
•Interference with brain development from early life infections is
consistent with the neurodevelopmental view of Sz.
•Childhood infections might have a priming effect on microglia.
•Thus, in the presence of an early life infection and a genetic
susceptibility, widespread activation of the microglia can occur.
•Activated Microglia can cause altered brain structure by the following
ways:
•a) aggressive synaptic pruning
•b) increasing the proportion of pro inflammatory cytokines
•c) causing activation of the innate and humoral immune system

73. MRI Evidence for
Neuroinflammation
•In a longitudinal study of Clinically High Risk
patients, it was found that higher levels of pro-
inflammatory markers at baseline predicted a
steeper rate of grey matter reduction in areas of
the PFC, in those who converted into fully
psychotic states.
•These grey matter changes are likely to reflect
the role of microglia in dendritic retraction and
synaptic pruning at a molecular level.

74. Immunity and Sz