Module 4.5

Question 1

Differentiate between and briefly describe key positive, negative and cognitive symptoms of schizophrenia.

Answer 1

• Schizophrenia is a psychiatric disorder that is expressed as a heterogeneous set of positive, negative and cognitive symptoms. Disease onset, in the form of reduced cognitive and social functioning, often begins in adolescence – before the occurrence of psychosis in adulthood
• Positive symptoms:
• Hallucination
• Disorganised behaviour
• Disorganised speech
• Delusions
• Negative symptoms:
• Inability to feel pleasure
• Loss of initiative
• Social withdrawal
• Affective flattening
• Cognitive symptoms:
• Impaired working memory
• Difficulty focusing
• Diminished executive function

Question 2

Describe how normal brain development occurs.

Answer 2

• The fusion of sperm and egg membranes:
• Triggers ions fluxes across the egg membrane
• Creates blocks to the entry of additional sperm into the egg
• Changes in the pH of the egg cytoplasm
• Increases egg metabolism and stimulates protein synthesis
• Initiates the rapid series of cell divisions that produce a multicellular embryo
• Complete cleavage (frogs):
• Cleavage furrows divide the zygote completely (initial cleavage furrow divides the egg into two cells, then 4,8,16 etc)
• Mammalian rotational cleavage (humans)
• The egg divides to form a blastocyst through intermediate steps of 2-cell blastomere and pre-blastocyst morula
• The blastocyst then undergoes gastrulation through which the cells of the inner cell mass differentiate into three primary germ cell layers:
   Ectoderm layer: these cells become the epidermis of the skin (outer layer)
• Neural ectoderm: special region of ectoderm that becomes the nervous system
• Endoderm: inner layer, these cells become the lining of our internal organs
  Mesoderm: these cells become muscle, blood, bone, connective tissue (the parts between the outer and inner layers
• Neurulation: (neural plate)
• 1) At the start of neurulation, the ectoderm of the neural plate is flat and the edges of the neural plate form ridges called neural folds
• 2) The neural plate invaginates and the folds fuse together forming the neural tube
• 3) The cells of the neural ridges become neural crest cells, which populate a specific region of the neural tube under the epidermis and also migrate to other parts of the body
• Terminology:
• Sagittal section: splitting the embryo in half
• Head end (rostral/anterior)
• Tail end (Caudal/posterior)
• Rostral neural tube (30 days):
• Optical vesicle: forms eye
• The coudal end forms cranial and spinal ganglia/cord
• Rostral (midbrain, forebrain, optic vesicle, neural tube)
• Rostral neural tube (60 days):
• The forebrain has divided into the Diencephalon and Telencephalon;
   Diencephalon: inner core of the forebrain develops into the thalamus and hypothalamus (major relay centres)
   Telencephalon: develops into the cerebrum, majority of cerebral hemispheres including outer cerebral cortex
• Rostral neural tube (180 days):
• Forebrain: cerebrum
• Midbrain: includes centres that integrate motor and sensory information
• Hindbrain: Cerebellum, Pons, Medulla
• Caudal – spinal cord

Question 3

Compare gross brain anatomy in healthy controls and patients with schizophrenia.

Answer 3

• Mechanisms:
• Schizophrenia involves abnormal neurodevelopment arising from a complex interplay between genetic and environmental risk factors
• The disorder is thought to be characterised by impaired function and connectivity of specific neural cell populations rather than gross brain pathology
• For instance, pharmacological therapies and genetic and post-mortem brain studies have implicated dopamine, N-methyl-D-aspartate (NMDA) and y-aminobutyric acid (GABA) signalling in the pathophysiology of schizophrenia

Question 4

Describe phases of neural development

Answer 4

• In order for all arts of the nervous system to develop correctly, there are 4 key phases of neural development that must occur:
• Genesis of neurons – neural stem cells give rise to neural progenitors and these differentiate into specific neural cells, this process is tightly controlled and leads to the genesis of the right neurons at the right time and right place
• Outgrowth of axons and dendrites – these are guided to their correct locations to make contact with other neurons or tissues
• Synapse formation – in order for neurons to communicate with other cells they must form synapses
• Refinement of synaptic connections – initially more neurons and synapses are generated but through programmed cell death of these neurons and synaptic pruning, the mature anatomy is defined
• Cerebral cortex (step 1: genesis of neurons)
• Highly layered structure, forms in an inside-out manner such that the early born neurons form the deepest layer of the cortex
• Coronal section through a developing cerebral cortex:
   Cortical neurons are generated in the ventricular proliferative zone (the region closest to the fluid filled ventricles of the developing brain, the lumen of the neural tube)
   New neurons are generated in the ventricular proliferative zone and migrate up along the process of radial glial cells, to get to their final location within the cortex
• Outgrowth of axons and dendrites (Step 2)
• The neurons extend their axons and dendrites, these processes are guided by where they need to go by mechanism that either attract or repel the growing axons
• Once the axon growth cone (end of axon that detects signals) finds its target neuron, two-way communication is involved in establishing synapses between the axon of the growing neuron and the target cell
• Two membranes become adherent to one another through various cell adhesion molecules that link the cell cytoskeleton of both cells (axon cone and dendrite)
• One region then becomes the synaptic junction and further maturation leads to the protrusion of the dendrite to form a dendritic spine which is surrounded by adhesion junctions

Question 5

Describe the structure and function of neurons and briefly summarise the electrical and chemical components of neural signalling.

Answer 5

• The neuron is a cell – has a nucleus and a cell membrane and organelles
• Dendrites receive signals which are integrated in the cell body and then the axon transmits the signal
• Action potential triggers the release of synaptic vesicles into the synaptic cleft
• The vesicles contain neurotransmitter and so different neurons will use different neurotranmitters depending on their function
• Synapses can be excitatory or inhibitory:
• Excitatory synapse will depolarise the postsynaptic membrane
• Inhibitory synapse will hyperpolarise or prevent depolarisation of postsynaptic membrane
• Three key amino acids:
• Glutamate – usually excitatory
• Glycine
• GABA – usually inhibitory
• Monoamines – dopamine, norepinephrine, serotonin

Question 6

Describe the dopamine hypothesis of schizophrenia and the mesolimbic and mesocortical dopamine signalling pathways.

Answer 6

• Dopamine hypothesis: administration of dopamine antagonists or drugs that bind to dopamine receptors, blocking the dopamine signalling reduce some of positive symptoms associated with schizophrenia
• The key dopaminergic neurons involved in schizophrenia are located in the midbrain in a region called the ventral tegmental area (VTA)
• The dopaminergic neurons project via four key pathways:
• Mesolimbic pathway and Mesocortical pathway are relevant to schizophrenia
• Mesolimbic pathway: projects to the limbic system, NAcc (nucleaus accumbens of striatum) – this area of the brain is involved in reward and addictive behaviours
• Mescortical pathway: projects to the cortical, region of the cortex involves in cognitive control, motivation and emotional response

Question 7

Summarise the role of genetics in the aetiology of schizophrenia.

Answer 7

• Biased cognitive schema: disrupted thought processes and core beliefs that can be biased towards a belief related to fear for example, leading to positive symptoms such as paranoia and delusions
  Diagram

Question 8

Describe the neurodevelopmental hypothesis of schizophrenia.

Answer 8

the etiology of schizophrenia may involve pathologic processes, caused by both genetic and environmental factors, that begin before the brain approaches its adult anatomical state in adolescence.