Glu, Schizophrenia and Alzheimer's Disease

Question 1

Flaws in the DA hypothesis of schizophrenia

Answer 1

Mismatch between dopamine antagonist receptor binding and effects: locomotor effects: sedation, decreased motor activity very quick i.e. minutes; antipsychotic effect takes much longer i.e weeks (underlying processes)
Schizophrenics with predominantly negative symptoms respond poorly or not at all to typical first generation antipsychotics (FGA) (thus don’t solve underlying cause)
Schizophrenics develop hypofrontality: reduce function of frontal lobe of neocortex
(associated with poor working memory)
Regional blood flow during a working memory task (133Xe dynamic SPECT), made worse by typical antipsychotics
Apomorphine (dopamine agonist) reversed the reduction in cerebral blood flow associated with hypofrontality and schizophrenics, due to a decrease in dopaminergic neurotransmission prefrontal areas in schizophrenia

Question 2

phencyclidine (PCP): drug of abuse a.k.a. Angel dust

Answer 2

originally thought to be new wonder drug: produces a dissociative state; loss of pain perception, but patient remains conscious
Acute doses produce auditory hallucinations, disorientation, paranoia, panic and intense aggression in normal subjects and potentiates symptoms in schizophrenics
Heavy abuse can trigger an irreversible psychosis: neural damage?
PCP is an NMDA receptor antagonist, PCP blocks NMDA receptor channels at a dose that also produces psychosis

Question 3

Effects of PCP and the primate brain (Jentsch et al., 1997)

Answer 3

Vrvet monkeys given PCP (0.3mg.kg) chronically for two weeks develop persistent cognitive deficits consistent with the negative symptoms of schizophrenia: poor performance on tests of frontal lobe function-hypofrontality; decreased dopaminergic utilisation-dorsolateral, prefrontal and pre-limbic cortex not NAc; ameliorated by atypical antipsychotic clozapine treatment
Chronic administration of PCP produces effects more consistent with schizophrenia in terms of both positive and negative symptoms

Question 4

L-Glu site (competitive)

NMDA receptor antagonist

Answer 4

2-amino-5-phosphonopentanoate (D-AP5)

Question 5

Glycine site (competitive)
NMDA receptor antagonist

Answer 5

5,7-Dichlorokynurenic acid (5,7-DCKA): 5,7-Dichloro -4-hydroxyquinoline-2-carboxylic acid

Question 6

Open channel blockers

Answer 6

Ketamine
Phencyclidine
MK-801

Question 7

When are open channel blockers effective?

Answer 7

These blockers are only effective if channel open i.e. undergoing activation by agonist aka use dependent

Question 8

The Glutamate/NMDA-R hypofunction hypothesis

Answer 8

Acute NMDA-R receptor ion channel blockade causes psychotic state in humans
Long term administration of NMDA-R antagnosists leads to pathology in prefrontal cortex similar to schizophrenics
50% risk factor in monozygotic twins: decreased NR1 (fewer functional NMDA-Rs); increased DAOO (increase breakdown of serien (glycine site ligand); increased neuregulin-ErbB4 signalling (regulates NMDA-R breakdown)

Question 9

Animal models of schiziphrenia

Answer 9

NR1 knockdown mouse: expresses 5% of normal NR1 levels (complete KO fatal); insensitive to PCP; social withdrawal (-ve); increased locomotor activity and stereotypy (+ve); respond to haloperidol and clozapine

Question 10

NMDA-Rs can only function as

Answer 10

heteromers

Question 11

Targeting NMDA-R glycine site

Answer 11

High dose glycine or low dose glycine + antipsychotics, similar seen with D-serine
Exception is glycine with clozapine (occlusion?)

Question 12

Potential treatments for schizophrenia being investigated?

Answer 12

CNS GlyT inhibitors to increase endogenous glycine levels

Sacrosine

Question 13

KYNA

Answer 13

Selective antagonist at NMDA-Rs and alpha 7 nAChRs (psychosis and negative symptoms
Endogenous KYNA mimics PCP on VTA
5-% increase in CNS KYNA in schizophrenics
Stress induced KYNA increase greater in distress intolerant schizophrenics
Decrease KYNA in monkeys and rats improves cognitive function in spatial learning and working memory tasks

Question 14

Alzheimer’s Disease

Answer 14

A neurodegenerative disease characterised initially by an inability to form new memories (particularly semantic and episodic), gradual decline in cognitive function –> dementia
STM loss –> delusions, psychosis, aggression –> decline in motor function
Death usually secondary

Question 15

Gross pathology of AD

Answer 15

Cortical atrophy in frontal, parietal and temporal lobes including the hippocampus, occipital lobe mostly spared, narrowing gyri and wider sulci, enlarged lateral ventricles

Question 16

2 pathological hallmarks associated with AD

Answer 16

Plaques: dense core of extracellular deposits of beta amyloid protein
Tangles: intracellular accumulation of hyperphosphorylated tau

Question 17

Causes of AD

Answer 17

95% idiopathic (LOAD), 5% is genetic (EOAD)

Question 18

EOAD genetics

Answer 18

100 different mutations in APP or presenilin 1 or 2
APP- TM protein
Presenilin 1 and 2- catalytic subunit of gamma secretase

Question 19

EOAD mutations

Answer 19

increase the ration of beta amyloid 42 relative to beta amyloid 40

Question 20

beta amyloid 42

Answer 20

more rapid aggregation into alogomers, protofibrils etc (longer hydrophobic C-terminal?)

Question 21

Role of soluble beta amyloid

Answer 21

APP itself GPCR?
Soluble sAPPalpha/beta ectodomains (plasticity?)
Picomolar soluble beta amyloid increases LTP, increase presynaptic Ca2+ synaptosomes in Hip, mediated by alpha 7 nAChR

Question 22

Role of soluble beta amyloid in AD

Answer 22

Idea that higher concentrations increase Glu uptake, increase EC Glu and activate NR2B NMDA-Rs thus decreasing LTP, functional antagonist at alpha 7 nAChR

Question 23

AD and memantine

Answer 23

Severe AD
Decreases rate of deterioration rather than improving existing function
Acts on NMDA-Rs, 5-HT3-Rs, nACh-Rs, D2-Rs, sigma1 Rs
Low affinity open channel blockers