Social Behavior in C. elegans.

Mutation in a neuropeptide-Y-like protein; the NPR-1 receptor. In mammals, important for “feeding”.

Clumping is controlled by an unknown neuropeptide acting through the receptor.

Secretion of the neuropeptide is probably regulated by food.

Proposed Model:

Dispersing strains have a repellant response (mediated by NPR-1 receptor) that masks the attractant response.

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The Sleep Disorder Canine Narcolepsy is Caused by a Mutation in the Hypocretin (Orexin) Receptor 2 Gene.
L. Lin et al., Cell 98 365 1999

Narcolepsy in orexin Knockout Mice: Molecular Genetics of Sleep Regulation.

RM Chemelli et al., Cell 98, 437 1999

Narcolepsy: debilitating, neurological disorder characterized by:

Sleep attacks

Episodic loss of muscle tone (cataplexy)

Hypnogogic hallucinations

Abnormal sleep-wake cycle

The Sleep Disorder Canine Narcolepsy is Caused by a Mutation in the Hypocretin (Orexin) Receptor 2 Gene.
L. Lin et al., Cell 98 365 1999

"Reduced Number of Hypocretin Neurons..."

Reduced Number of Hypocretin Neurons in Human Narcolepsy

TC Thannickal et al., Neuron 27; 469 2000

Distribution of Cells in Perifornical and Dorsomedial Hypothalamic Regions of Normal and Narcoleptic Humans

On average, narcoleptics have 7% of the Hcrt cells seen in normals

C and D – low power covering regions shown in grey at top

E and G – normal subjects

F and H – narcoleptic subjects

Most human narcolepsy is NOT familial; is discordant in identical twins; and NOT linked to mutations in hypocretin.

Narcolepsy: summary

Hypothetical Effect of Blunted Hcrt Activation:

Monoaminergic Nuclei of the Brainstem: induce cataplexy.

Cholinergic Brainstem and Basal Forebrain: cause sleepiness associated with narcolepsy.

Dense Hcrt Projections to the Suprachiasmatic Nucleus: reduced amplitude of circadian sleep rhythms, and thereby increased sleepiness during the day and interrupted sleep at night.

The Essential Role of Hippocampal CA1 NMDA Receptor-Dependent Synaptic Plasticity in Spatial Memory
JZ Tsien, PT Huerta, and S. Tonegawa, Cell 87 1327 1996.

Summary of Hippocampal Studies since 1957:

Required for certain kinds of memory; spatial in rodents; facts and faces in humans.

Rodent hippocampal neurons are “place cells”; ‘fire’ when animal moves into marked area.

Hippocampal synapses exhibit LTP (paradigm for synaptic plasticity).

Tsien et al: use cre/loxP recombination system to delete NMDA receptor function only in CA1 subregion.

THUS: By effecting CA1-specific NMDA receptor inactivation, the studies relate synaptic plasticity to neuronal activity (place fields) and to spatial learning.

The Essential Role of Hippocampal CA1 MNDA Receptor-Dependent Synaptic Plasticity in Spatial Memory

JZ Tsien, PT Huerta, and S. Tonegawa, Cell 87 1327 1996.

The Essential Role of Hippocampal CA1 NMDA Receptor-Dependent Synaptic Plasticity in Spatial Memory
JZ Tsien, PT Huerta, and S. Tonegawa, Cell 87 1327 1996.

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Most Human Behaviors are Likely to be Genetically Complex: i.e., result from the complex interaction of multiple genes together with non-genetic (environment; stochastic) factors.

Genetics of Autism

Twin Studies

Monozygotic twins are about 78% concordant for autism and spectrum disorders.

Dizygotic twins are about 17% concordant. Recurrence Risk

Approximately 3% of affected probands have an affected sibling with autism (15% for autism + spectrum).

Relative risk

Recurrence risk/prevalence

50-100 fold increase risk to first-degree relatives compared to general population.

Genetics of Autism

Very high: MZ:DZ twin ratio

Relatively low: ‘sibling-risk’ (recurrence risk)

Very high: ‘relative risk’

Interpretation: Autism is strongly influenced by genetic factors; multiple genes contribute; each single gene effect is probably small; epistatic interactions are likely.

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Heritability of Psychiatric Disorders
Degree to which heritable (genetic) factors influence expression of disease or trait

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Alzheimer’s Disease is currently the best example of a complex disease with known genetic etiology.

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Apolipoprotein E - e4

e4/e4 AD patients show markedly more APP deposition in plaques relative to non-e4 AD patients

ApoE e4 binds BA4 peptide with greater avidity than e3 isoform.

ApoE e4 shows significant allelic association in familial and sporadic late onset AD, and in familial early onset AD.

e4 heterozygote is 3X more likely to be affected than e2/e3 or e3/e3

e4 homozygote is 8X more likely to be affected

Conclusion: ApoE e4 gene dose is a major risk factor for late (and possibly early) onset AD. Inheritance of two e4 alleles is not necessary and probably not sufficient to cause AD.

Slide 36


	Mutation in a neuropeptide-Y-like protein; the NPR-1 receptor. In mammals, important for “feeding”.
	Clumping is controlled by an unknown neuropeptide acting through the receptor.
	Secretion of the neuropeptide is probably regulated by food.

	Proposed Model:

		Dispersing strains have a repellant response (mediated by NPR-1 receptor) that masks the attractant response.


	Narcolepsy in orexin Knockout Mice: Molecular Genetics of Sleep Regulation.
	RM Chemelli et al., Cell 98, 437 1999

	Narcolepsy: debilitating, neurological disorder characterized by:
	Sleep attacks
	Episodic loss of muscle tone (cataplexy)
	Hypnogogic hallucinations
	Abnormal sleep-wake cycle


	Reduced Number of Hypocretin Neurons in Human Narcolepsy
	TC Thannickal et al., Neuron 27; 469 2000


	Distribution of Cells in Perifornical and Dorsomedial Hypothalamic Regions of Normal and Narcoleptic Humans

	On average, narcoleptics have 7% of the Hcrt cells seen in normals
	C and D – low power covering regions shown in grey at top
	E and G – normal subjects
	F and H – narcoleptic subjects

	Most human narcolepsy is NOT familial; is discordant in identical twins; and NOT linked to mutations in hypocretin.


	Hypothetical Effect of Blunted Hcrt Activation:

	Monoaminergic Nuclei of the Brainstem: induce cataplexy.

	Cholinergic Brainstem and Basal Forebrain: cause sleepiness associated with narcolepsy.

	Dense Hcrt Projections to the Suprachiasmatic Nucleus: reduced amplitude of circadian sleep rhythms, and thereby increased sleepiness during the day and interrupted sleep at night.


	Summary of Hippocampal Studies since 1957:

		Required for certain kinds of memory; spatial in rodents; facts and faces in humans.
		Rodent hippocampal neurons are “place cells”; ‘fire’ when animal moves into marked area.
		Hippocampal synapses exhibit LTP (paradigm for synaptic plasticity).

		Tsien et al: use cre/loxP recombination system to delete NMDA receptor function only in CA1 subregion.

		THUS: By effecting CA1-specific NMDA receptor inactivation, the studies relate synaptic plasticity to neuronal activity (place fields) and to spatial learning.


	Twin Studies
	Monozygotic twins are about 78% concordant for autism and spectrum disorders.
	Dizygotic twins are about 17% concordant. Recurrence Risk
	Approximately 3% of affected probands have an affected sibling with autism (15% for autism + spectrum).
	Relative risk
	Recurrence risk/prevalence
	50-100 fold increase risk to first-degree relatives compared to general population.



	Very high: MZ:DZ twin ratio
	Relatively low: ‘sibling-risk’ (recurrence risk)
	Very high: ‘relative risk’

	Interpretation: Autism is strongly influenced by genetic factors; multiple genes contribute; each single gene effect is probably small; epistatic interactions are likely.


	e4/e4 AD patients show markedly more APP deposition in plaques relative to non-e4 AD patients
	ApoE e4 binds BA4 peptide with greater avidity than e3 isoform.
	ApoE e4 shows significant allelic association in familial and sporadic late onset AD, and in familial early onset AD.
		e4 heterozygote is 3X more likely to be affected than e2/e3 or e3/e3
		e4 homozygote is 8X more likely to be affected

	Conclusion: ApoE e4 gene dose is a major risk factor for late (and possibly early) onset AD. Inheritance of two e4 alleles is not necessary and probably not sufficient to cause AD.