John Rubenstein, UCSF BBRF Webinar May 13, 2014 Hypothesis: Many - - PowerPoint PPT Presentation

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John Rubenstein, UCSF BBRF Webinar May 13, 2014 Hypothesis: Many - - PowerPoint PPT Presentation

Oct 03, 2022 654 likes •1.27k views

"Understanding Brain Development as a Foundation for Understanding Brain Diseases" John Rubenstein, UCSF BBRF Webinar May 13, 2014 Hypothesis: Many Psychiatric Disorders Are Caused by Dysfunction of Brain Circuits Due to Abnormal

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John Rubenstein, UCSF

BBRF Webinar May 13, 2014 "Understanding Brain Development as a Foundation for Understanding Brain Diseases"

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Hypothesis: Many Psychiatric Disorders Are Caused by Dysfunction of Brain Circuits Due to Abnormal Development and/or Function of Specific Circuits

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Two General Types of Circuits

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Long Distance Circuits

From: Charles Gerfen

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Local Circuits

From: Oscar Marin

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Review of Major Steps in Brain Development

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Steps In Neural Development

Induction Neurulation Regional Patterning (anteroposterior, dorsoventral) Proliferation Migration (mediolateral patterning of the neural tube) Axon Pathfinding and Synapse Formation Myelination

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Steps In Neural Development

Induction* Neurulation* Regional Patterning (anteroposterior, dorsoventral) Proliferation Migration (mediolateral patterning of the neural tube) Axon Pathfinding and Synapse Formation Myelination

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Neurulation and Early Patterning Centers

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Patterning Centers in the Forebrain

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Steps In Neural Development

Induction Neurulation Regional Patterning (anteroposterior, dorsoventral)* Proliferation Migration (mediolateral patterning of the neural tube) Axon Pathfinding and Synapse Formation Myelination

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Blueprint of the Brain

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Transverse and Longitudinal Organization of the CNS

Neural Plate Neural Tube

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Monoamine Neurons: Specific Locations

Acetylcholine Histamine Norepinephrine Serotonin

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Steps In Neural Development

Induction Neurulation Regional Patterning (anteroposterior, dorsoventral) Proliferation* Migration (mediolateral patterning of the neural tube) Axon Pathfinding and Synapse Formation Myelination

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Progenitor Zones

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Steps In Neural Development

Induction Neurulation Proliferation Regional Patterning (dorsoventral)* Migration (mediolateral patterning of the neural tube) Axon Pathfinding and Synapse Formation Myelination

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Patterning Centers in the Forebrain

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Transcription Factors Which Regulate Regional Patterning And Differentiation of the Telencephalon “Dorsoventral” Subdivisions Of the Telencephalon

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Patterning of Regions and Neural Identity

Marín O, Rubenstein JL. Nat Rev Neurosci. 2001 Nov;2(11):780-90

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Steps In Neural Development

Induction Neurulation Regional Patterning (anteroposterior, dorsoventral) Proliferation Migration (mediolateral patterning of the neural tube)* Axon Pathfinding and Synapse Formation Myelination

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Radial Migration in the Telencephalon

Radial Migration of Projection Neurons

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Radial Migration to Build the Cortex

From: Lui JH, Hansen DV, Kriegstein AR. Cell. 2011 Jul 8;146(1):18-36

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Tangential Migration of Interneurons

Marín O, Rubenstein JL. Nat Rev Neurosci. 2001 Nov;2(11):780-90

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Radial and Tangential Migration in the Telencephalon

Radial Migration of Projection Neurons Tangential Migration of Local Circuit Neurons

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Assembly of Circuits

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Cortical Circuits: Projection Neurons and Interneurons

Marín O. Nat Rev Neurosci. 2012 Jan 18;13(2):107-20.

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Steps In Neural Development

Induction Neurulation Regional Patterning (anteroposterior, dorsoventral) Proliferation Migration (mediolateral patterning of the neural tube) Axon Pathfinding and Synapse Formation* Myelination

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Axons Grow Transversely or Longitudinally Follow Specific Molecular Landmarks

Transverse Pathways

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Longitudinal Pathways: Branch at Functionally Related Nuclei

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Corpus Callosum Autism Traits in Individuals with Agenesis of the Corpus Callosum

Lau YC, Hinkley LB, Bukshpun P, Strominger ZA, Wakahiro ML, Baron-Cohen S, Allison C, Auyeung B, Jeremy RJ, Nagarajan SS, Sherr EH, Marco EJ. J Autism Dev Disord. 2012 Oct 5.

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Steps In Neural Development

Induction Neurulation Regional Patterning (anteroposterior, dorsoventral) Proliferation Migration (mediolateral patterning of the neural tube) Synapse Formation and Function* Myelination

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Molecular Defects at the Synapse in Autism

Walsh, Morrow and Rubenstein, 2008

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Steps In Neural Development

Induction Neurulation Regional Patterning (anteroposterior, dorsoventral) Proliferation Migration (mediolateral patterning of the neural tube) Synapse Formation and Function Myelination, and Functions of Non-neural cells*

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Models For Mechanisms of Neurodevelopmental Disorders

  • 1. Detection of salient synaptic

information – signal/ noise processing (excitation/inhibition balance)

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Epilepsy and Cognitive Dysfunction in Autism

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“Tuning” Curve for Optimal Neural Circuit Function

Low Excitation High Inhibition Low Noise but

Optimal Function

High Excitation Low Inhibition High Noise

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Changes in the Numbers and Functions

  • f GABA Interneurons Can

Alter the Tuning Curve

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Autistic-like behavior in Scn1a+/- mice.

Han et al. (Bill Catterall Lab)

.

  • Nature. 2012 Sep 20;489(7416):385-90
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Scn1a: Sodium Channel. Model of Dravet Syndrome (Epilepsy, Cognitive Dysfunction with Autistic Behaviors).

.

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Autistic-like behavior in Scn1a+/- mice was rescue by enhanced GABA-mediated neurotransmission (clonazepam treatment).

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Projection and Local Circuit Neuron Defects in the Prefrontal Cortex in Schizophrenia

From the work of the Lewis, Jones, Benes labs. Reviewed in Frankle et al., 2003

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Models For Mechanisms of Neurodevelopmental Disorders

  • 2. Cerebral hyperplasia secondary to

increased growth factor signaling.

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Transient Cortex Overgrowth in Some Autistic Individuals

Work of several labs, including:

  • E. Courchense
  • J. Piven
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Growth Factor Expression in the Forebrain

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Models For Mechanisms of Neurodevelopmental Disorders

  • 3. Dysfunction of cortical-basal

ganglia circuits

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Cortex-Basal Ganglia-Thalamus Circuit

Descending Pathways

From: Charles Gerfen

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Prefrontal Cortex-Basal Ganglia-Thalamus Circuit

Ascending Pathways

Adapted from Charles Gerfen

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Shank3 mutant mice display autistic-like behaviors and striatal dysfunction

Peça J, Feliciano C, Ting JT, Wang W, Wells MF, Venkatraman TN, Lascola CD, Fu Z, Feng G.

  • Nature. 2011 Apr 28;472(7344):437-42.
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Shank3 mRNA is highly expressed in the striatum. Shank3 Regulates Assembly of Glutamate Receptor Complexes

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Glutamate receptor protein subunits GluR2, NR2A and NR2B are reduced in striatal synapses

  • f Shank3−/− mice.
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Schizophrenia Defects in the Prefrontal Cortex- Basal Ganglia-Thalamus Circuit

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Prefrontal Cortex

  • Prefrontal Hypofunction and Hypoplasia
  • Interneuron Defects:

Reduced GAD expression

  • Projection Neuron Defects:

Reduced GABA-Receptor Expression

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Basal Ganglia

  • Striatal (Caudate) Hypoplasia

Thalamic Defects

  • Mediodorsal Nucleus Hypoplasia
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Models For Mechanisms of Neurodevelopmental Disorders

  • 4. The male brain/genotype

Y Chromosome Sex steroids

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Perhaps the female brain is protected from the genetic and environmental influences that lead to the 4:1 male:female ratio in autism and

  • ther childhood disorders.
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In evaluating etiologies and therapies consider the steps and mechanisms in neurodevelopment

Induction Neurulation Regional Patterning (anteroposterior, dorsoventral) Proliferation Migration (mediolateral patterning of the neural tube) Synapse Formation and Function Myelination, and Functions of Non-neural cells

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And always consider the effects of those defects on the development and function

  • f circuits

From: Charles Gerfen