| MAOI | |
| TCA | |
| SSRI | |
| Lithium | |
| CRF, SP antagonists | |
| Benzodiazepines | |
| TCA | |
| SSRI | |
| CRF, SP antagonist | |
Genetic and Environmental Factors in Anxiety Disorders
| Behavioral validation | |
| Multiple behavioral and physiological tests | |
| Factor analysis (covariance analysis) | |
| Pharmacological validation | |
| Response to therapeutically active drugs but not to inactive drugs | |
| Comparable pharmacokinetic profiles |
Anatomy of the serotonergic system
Construction of 5-HT1AR KO mice
Does forebrain receptor reverse the phenotype of the 5-HT1A KO mice?
| Forebrain receptor sufficient to reverse knockout phenotype | |
| Adult receptor not required to maintain rescue | |
| Expression during development critical to rescue |
Evidence for developmental role of 5-HT
Increased excitability in CA1 pyramidal neurons of knockout mice
5-HT1AR function:
development vs. adulthood
long term molecular and morphological changes
Mechanism of action of antidepressants
| Change of the setpoint of monoamine transmission | ||||
| Plastic changes occurring in the limbic target areas of monoaminergic projections (Hipp., Amy., Ctx) | ||||
| Halt hippocampal atrophy | ||||
| Prevent stress-induced dendritic shrinkage | ||||
| Increase hippocampal neurogenesis | ||||
Hippocampal Atrophy In Recurrent Major Depression
Behavioral tests to detect antidepressant action
| Tail suspension test | |
| Forced swimming test | |
| Ultrasonic vocalization | |
| Learned helplessness | |
| Chronic unpredictable stress | |
| Novelty-suppressed feeding | |
Parkinson’s Disease: Clinical Characteristics
| Disease of aging: | |||
| -Incidence: Overall 20/100,000 | |||
| Age 70 120/100,000 | |||
| Clinical Features: tremor, rigidity, slowness of movement, postural instability | |||
| Pathology: substantia nigra pars compacta, locus coeruleus, nucleus basalis of Meynert, olfactory bulb | |||
Parkinson’s Disease: Environment
| 1918: influenza pandemic | |
| 1983: MPTP |
| Clinical: All cardinal manifestations of idiopathic PD. | |
| Pharmacology: Respond to dopaminergic drugs | |
| Pathology: Ventral substantia nigra, locus coeruleus, hypothalamus | |
| Pathogenesis: Mitochondrial dysfunction, oxidative stress | |
Parkinson’s Disease and a-Synuclein
| Mutations produce autosomal dominant PD | |
| Abundant in Lewy bodies | |
| Present in Glial Cytoplasmic Inclusions (MSA) | |
| Accumulates in Hallevordan-Spatz disease | |
| Highly abundant in CNS | |
| Concentrated in presynaptic terminals near vesicles | |
| Lipid and vesicle binding | |
| Conformational change upon lipid binding | |
| Modulation of rate of recycling of the readily releasable pool | |
a-Synuclein Function: Vesicles
What is the nature of a-synuclein dysfunction that leads to dopamine neuron degeneration ?
a-Synuclein: Gene Targeting Strategy
a-Synuclein:
Knock Out Characterization
a-Synuclein Null Mice:
Resistance to MPTP-Induced Neurodegeneration
A brief introduction to HD (1):
| George Huntington, 1872 | |||
| Age of onset: 40 to 50 yrs | |||
| Progressive | |||
| Motor: chorea, dystonia | |||
| Psychiatric: depression, anxiety, suicide | |||
| Cognitive changes: declarative memory, dementia | |||
| Autosomal dominant inheritance | |||
Striatal specific atrophy of HD
A brief introduction to HD (2):
| The HD gene, IT15 (HDCRG, 1993) | ||||
| Promoter: house keeping gene? | ||||
| Conserved to Fugu puffer fish | ||||
| Gene KO studies | ||||
| Nasir et al., Zeitlin et al., Duyao et al. | ||||
| Gene product, huntingtin (htt) | ||||
| Large protein in complex | ||||
| Function: unknown | ||||
| Ubiqutious expression | ||||
| Cleavage by calpain and caspase-3 | ||||
A brief introduction to HD (3):
| Triplet repeat expansion (C-A-G) | ||
| Unaffected, n= 4 to 35; Pathogenic, n > 37 | ||
| Triplet repeat disorders (17) | ||
Effect of CAG expansion on htt
| CAG expansion is translated | ||
| CAG encodes for glutamine (Q) | ||
| No loss of function | ||
| Patients homozygote for HD mutation | ||
| Dominant gain of function | ||
| Bates’ R6 transgenic (R6/2) | ||
| Mangiarini et al. (1995) Cell | ||
| cDNA transgenic | ||
| Reddy et al. (1998) Nat Genet 20, 198-202 | ||
| N171 transgenic | ||
| Schilling et al. (1999) Hum Mol Genet 8, 397-407 | ||
| YAC transgenic | ||
| Hodgson et al. (1999) Cell 23, 181-92 | ||
| (CAG)n knock-in | ||
| Wheeler et al. (1999) Hum Mol Genet 8, 115-22 | ||
| Shelbourne et al. (1999) Hum Mol Genet 8, 763-74 | ||
| Lin et al. (2001) Hum Mol Genet 10, 137-44 | ||
| Davies et al., 1997 | ||
| Intranuclear aggregates | ||
| “Dark bodies” (Roizin, 1977) | ||
| DiFiglia et al., 1997 | ||
| Intranuclear aggregates | ||
| cytoplasmic aggregates | ||
| Scherzinger et al., 1997 | ||
| Ribbon-like morphology | ||
| Is continuous expression of the transgene required for the HD-like phenotype? | |
| Is the HD-like phenotype reversible? |
Inducible mouse model
A
model with a switch
Intranuclear & cytoplasic aggregates
HD mice demonstrate a progressive clasping phenotype
| Expression of exon1 CAG94 leads to an HD-like phenotype |
| 2 mg dox/ ml 5% sucrose | ||
| Duration: 16 weeks | ||
| Halt progression | ||
| Amelioration | ||
| Expression of exon1 CAG94 leads to an HD-like phenotype | |
| Abolishing gene expression for 16 weeks leads to a reversal of aggregate formation and motor phenotype |
Primary striatal cultures from HD94 mice
| Kinetics of aggregate formation and reversion | |
| Possible mechanisms for aggregate reversion |
| In vitro | ||
| “Soluble” exon1CAG94 clears within 2 to 3 days of shutting down gene expression. | ||
| Aggregates clear within 5 days of shutting down gene expression (3d + 2d). | ||
| Aggregate clearance is inhibited in the presence of lactacystin (proteasome). | ||