Theories of Schizophrenia

Dr Parth Goyal

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

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.

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.

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.

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.

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.

Dopamine Pathways • 1) Mesolimbic Pathway

• 2) Mesocortical Pathway

• 3) Nigrostriatal Pathway

• 4) Tuberoinfundibular Pathway

• 5) Thalamic Pathway

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.

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.

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.

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.

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.

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.

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.

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.

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.

Presynaptic Auto receptors (mGluR 2,3)

Inotropic Glutamate Receptors

• They are located post-synaptically and include:

• NMDA, AMPA, Kinate family of receptors.

Pharmacology of Glutamate Receptors

Physiologic Roles of Glutamate

• There are 3 main physiologic functions of Glutamate:

• a) Synapse formation and Synapse Maturation

• b) Synaptic Plasticity

• c) Neurotoxicity.

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.

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.

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.

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.

Differential actions of AMPA and NMDA Receptors.

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

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.

Glutamate mediated Excitotoxicity.

Glutamate and Schizophrenia

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.

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.

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.

Linking NMDA Hypofunction with Dopamine Hypothesis

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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

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.

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.

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.

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.

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.

Synaptic Pruning

Linking the 2 models.

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.

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.

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.

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

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.

Immunity and Sz