Cellular NeurobiologyBIPN140

1st Midterm Exam Ready for PickupBy the elevator on the 3rd Floor of Pacific Hall (waiver)

Exam Depot Window at the north entrance to Pacific Hall (no waiver)Mon-Fri, 10:00 AM to 4:00 PM

Regrade request is accepted till Nov 14th. Please contact the IA who graded the question directly.

Second midterm is next Tuesday!! Covers lectures 7-12 (Synaptic transmission, NT & receptors, intracellular signaling & synaptic plasticity).

Review session is on Monday (Nov 14th) before midterm 6:00-8:00 PM at 3500 Pacific Hall. Please come with questions.

PS 6 is now posted on the website2015 Problem sets #4~ #6 and 2nd midterm are also posted!

Chih-Ying’s Office Hour: Monday, 1:00-2:00 PM, Bonner Hall 4146

BIPN140 Lecture 13: Synapse Formation (Synaptogenesis)

Su (FA16)

1. Neuromuscular Junction (NMJ) Development

2. Synaptogenesis at Central Synapses

Ultrastructural Image of an NMJ Active Zone

Basal Lamina

Junctional fold

Active zone

(Kandel et al., Principles of Neural Science, 5th Edition, Fig 55-7)

(Kandel et al., Principles of Neural Science, 5th Edition, Fig 55-7)

NMJ Develops in Sequential Stages (Fig. 23.11)

Immature:Multiple innervation

Mature:Monosynaptic innervation

Post- (muscle fiber) => laminin => Presynaptic specialization

(Kandel et al., Principles of Neural Science, 5th Edition, Fig 55-9)

(Kandel et al., Principles of Neural Science, 5th Edition, Fig 55-11)

AChR clusters

Pre- (MN terminals) => Agrin => Postsynaptic AChR clustering

(Kandel et al., Principles of Neural Science, 5th Edition, Fig 55-12)

Junctionalnucleus

Extra-junctional nucleus

neuregulin

A muscle fiber has multiple nuclei that can produce gene product independently.

Pre to post signaling: Neuregulin (+) and Ach (-)

Depolarization

Elimination of Multiple Innervation (Fig. 23.12)

Elimination of multiple innervation in the PNS. Live imaging of the same NMJ:

At P11, two axons (blue & green) innervate the same muscle. AChR labeled in red.

By P12, the proportion of territory occupied by the green and blue axons has begun to shift, with the green axon terminal expands.

By P14, the blue axon has fully retreated, its synaptic terminal transformed into a large retraction bulb then fully withdrawn from the synaptic site.

Motor neuron #1Motor neuron #2AChR

Some Neuromuscular Synapses are Eliminated after Birth

Local blockade of AChR

Summary: NMJ Development

(Naguib et al., Anesthesiology 96, 202-231, 2002)

Central v.s. NMJ Synaptogenesis

(Kandel et al., Principles of Neural Science, 5th Edition, Fig 55-14)

NMJExcitatory

Central Synapse

Inhibitory Central

Synapse

Dendritic Spine Dendritic Shaft

Axon VaricosityAxon Varicosity

Presynaptic bouton: small axonal varicosities, ~1 m in size, establishing contacts with postsynaptic cells.

Active zone: presynaptic region where SV fusion can occur (visible in EM as a meshwork of proteins).

Postsynaptic density: opposing the active zone, clusters of NT receptors, channels, signaling molecules & scaffolding proteins.

Signaling Pathways Regulating CNS Synaptogenesis

(Waites, Craig & Garner, Annu Rev Neurosci, 2005)

Axo-dendritic synapse

Cell Adhesion Molecules Guiding Synaptic Specificity (23.4 & 8)

Potential Molecular Mediators of Synapse Identity (Fig. 23.9)

Inductive Factors for Synaptogenesis (Fig. 23.8)

Neurexin (pre-)-Neuroligin (post) Interaction Promotes Synaptic Differentiation

Ephrins and Eph Receptors (Fig. 23.4)

1. Filopodium extends from dendrite

2. Initial contact with axon terminal/branch (adhesive factors).

3. Inductive events: specific trans-synaptic acting components.

4. Maturation (asymmetric): (a) presynaptic active zones (b) postsynaptic scaffolds: clustering of receptors, segregated

receptor distribution, signaling molecules, ion channels, cytoskeletal reorganization, etc.

(c) increased NT release and receptor responsiveness

Developmental Sequence of Glutamatergic Synapses

Axo-dendritic synapse

Fig. 1. Exposure of mice to increased circuit activity reveals an NPAS4-depdendent regulation of inhibition in vivo.

Fig. 2. Behaviorally induced NPAS4 differentially regulates inhibitory synapse function across the somato-dendritic axis of pyramidal neurons.