Lecture 2: PRENATAL KYNURENINE EXPOSURE AND IMPAIRED PREFRONTAL MATURATION: IMPLICATIONS FOR SCHIZOPHRENIA Flashcards
SCHIZOPHRENIA
debilitating thought disorder.
Affects about 1-2% of the worldwide population across ethnic and cultural borders.
Schizophrenia is a Neurodevelopment disorder, but usually doesn’t’ manifest itself until the young adult stage
Positive Symptoms:
hallucinations; delusions
Negative Symptoms:
avolition; ambivalent affect
Cognitive Symptoms:
cognitive control or executive functions
Cognitive deficits are core symptoms:
- emerge in prodromal phase
- present in 1st degree relatives that are not schizophrenic
- predictive of outcome
unmet treatment need
avolition
Avolition is a psychological state characterized by general lack of drive, or motivation to pursue meaningful goals. A person may show little participation in work or have little interest in socializing. They may sit still for long periods of time.
ambivalent affect
Involves feeling one way when you should feel another way… ??
Typically, Schizophrenic Patients Present with 3 Clusters of Symptoms:
- Positive: hallucinations; delusions
- Negative: avolition; ambivalent affect
- Cognitive: cognitive control or executive functions
core symptoms
present in all cases, even long before the symptoms begin to show.
prodromal
relating to or denoting the period before the appearance of initial symptoms
EVIDENCE THAT SCHIZOPHRENIA IS A NEURODEVELOPMENTAL
DISORDER
Ø MANY RISK FACTOR GENES ARE ASSOCIATED WITH
DEVELOPMENT OF THE NERVOUS SYSTEM
Ø NEURONAL MIGRATION ERRORS IN NEOCORTEX AND
HIPPOCAMPUS.
Cell plate, Ventricular zone, Neuronal Transport….
Migration happens prenatally and in the early natal periods.
Ø DISRUPTION OF EXCITATORY/INHIBITORY BALANCE
Ø OBSTETRIC COMPLICATIONS AND IMMUNE CHALLENGES DURING PREGNANCY INCREASE RISK FOR DISEASE.
If mom gets sick while she’s pregnant, the risk for the child developing schizophrenia increases exponentially.
Ø ADOLESCENCE AS A RISK FACTOR FOR SYMPTOM
ONSET.
The early vulnerability and natural plasticity characteristic of the adolescent brain can cause the brain to transform.
Ø NEURODEVELOPMENTAL ANIMAL MODELS RECREATE
ASPECTS OF THE SCHIZOPHRENIC PHENOTYPE
STRATEGY UNDERLYING ANIMAL MODELING OF SCHIZOPHRENIA
Ø REPRODUCE SPECIFIC ELEMENT OF
PATHOPHYSIOLOGY IN SCHIZOPHRENIA (perinatal
elevations in brain kynurenic acid)
Ø REVEAL DEFICITS IN TASKS THAT MEASURE
COGNITIVE DOMAINS THAT ARE IMPAIRED IN
SCHIZOPHRENIA (working memory; cognitive
flexibility)
Ø DESIGN AND TEST DRUGS THAT REDUCE THE
PATHOPHYSIOLOGY AND ENHANCE COGNITION
The severity of the cognitive defects determines the struggle for the schizophrenic patient
Ironically, the cluster of systems that matter the most (are most influential and central to the disease) are the very same symptoms that schizophrenic medications are least effective at treating. The Cognitive symptoms are the core symptoms of schizophrenia. Cognitive symptoms are the most critical and the most universal of all the symptoms, but also the least treatable.
ROLE OF GLUTAMATE AND
ACETYLCHOLINE IN Schizophrenia
• NMDA receptor antagonists are psychotomimetic;
• NMDA and nicotinic receptor antagonists impair attention;
attentional set shifting; & working memory in rodents
•There is reduced expression of
nAChR and NMDAR mRNA in patients with Schizophrenia
Psychotomimetic
A drug with psychotomimetic actions mimics the symptoms of psychosis, including delusions and/or delirium, as opposed to just hallucinations.
Psychotomimesis is the onset of psychotic symptoms following the administration of such a drug.
NMDA receptor
The N-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function.
The NMDAR is a specific type of ionotropic glutamate receptor. NMDA (N-methyl-D-aspartate) is the name of a selective agonist that binds to NMDA receptors but not to other glutamate receptors. Activation of NMDA receptors results in the opening of an ion channel that is nonselective to cations with an equilibrium potential near 0 mV. A property of the NMDA receptor is its voltage-dependent activation, a result of ion channel block by extracellular Mg2+ & Zn2+ ions. This allows the flow of Na+ and small amounts of Ca2+ ions into the cell and K+ out of the cell to be voltage-dependent.
Calcium flux through NMDARs is thought to be critical in synaptic plasticity, a cellular mechanism for learning and memory. The NMDA receptor is distinct in two ways: first, it is both ligand-gated and voltage-dependent; second, it requires co-activation by two ligands: glutamate and either D-serine or glycine.
Receptor antagonist
Drug class A receptor antagonist is a type of receptor ligand or drug that blocks or dampens agonist-mediated responses rather than provoking a biological response itself upon binding to a receptor.
