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Method for identifying compounds which affect synaptogenesis

a technology of compound and synaptogenesis, applied in the field of molecules involved in synaptogenesis, can solve the problems of additional complexity in the formation of central excitatory synapses, and achieve the effects of increasing the number of excretory synapses

Inactive Publication Date: 2008-09-25
THE JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

Narp facilitates the formation of excitatory synapses by clustering AMPA receptors and increasing the number of synaptic connections, providing a therapeutic approach for disorders associated with decreased or increased Narp expression, such as Alzheimer's disease and epilepsy.

Problems solved by technology

An additional level of complexity in the formation of central excitatory synapses stems from the fact that two populations of neurons exist (termed spiny and aspiny) which receive excitatory input in mutually exclusive patterns (Sloper and Powell, 1979; Harris and Kater, 1994).

Method used

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  • Method for identifying compounds which affect synaptogenesis
  • Method for identifying compounds which affect synaptogenesis
  • Method for identifying compounds which affect synaptogenesis

Examples

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Effect test

example 1

Narp is Enriched at Excitatory Synapses in a Subpopulation of Neurons from Hippocampus and Spinal Cord

[0089]To study Narp protein, a rabbit polyclonal antibody was generated against a full length GST fusion protein of Narp. On western blot, this antibody recognized a single broad protein band centered at 56 kDa in rat brain, similar to the size of recombinant Narp expressed in detergent extracts of transfected HEK-293 cells. Narp protein was also detected as a similar sized triplet in rat testes, but not in other peripheral tissues. This restricted distribution of Narp protein parallels the Narp mRNA expression previously reported (Tsui et al., supra, 1996). The broadness of the Narp band in brain is consistent with the observation that Narp is glycosylated (Tsui et al., supra, 1996). In non-reducing gels, Narp migrates as a multimer, with a size greater than 220 kDa, consistent with the known ability of members of the pentraxin family to covalently multimerize through disulfide bon...

example 2

Transfected Narp Accumulates at Excitatory Synapses

[0096]In order to characterize the synaptic targeting of Narp in neurons, a C-terminal myc-tagged version of Narp (designated myc-Narp) was transfected into cultured spinal neurons (Dong et al., Nature 386:279-84, 1997). After 72 hours of expression, live staining with an anti-myc (mouse) antibody, followed by a FITC labeled anti-mouse secondary, was used to reveal the surface distribution of the transfected Narp. Subsequent staining of the same cells, after fixation and permeabilization, with an AMCA labeled anti-myc (rabbit) antibody was used to identify transfected neurons and their axons and dendrites, while GluR1 and GAD staining were used to identify excitatory and inhibitory synapses, respectively.

[0097]Staining of transfected neurons indicated that myc-Narp, similar to endogenous Narp, was distributed throughout the somato-dendritic domain of the transfected neuron and was also specifically localized to excitatory synapses. ...

example 3

Synaptic Narp is Derived from Both the Presynaptic and Postsynaptic Neuron

[0099]Since only 1 to 3% of the neurons in a given experiment are transfected by the procedure described above, it was relatively easy to distinguish myc-Narp that came from the postsynaptic cell (surface stain associated with the large proximal processes of an isolated transfected cell) from myc-Narp originating from the presynaptic cell (surface stain associated with a solitary thin process coursing over a non-transfected cell body or dendrite which is not in continuity with any visibly transfected cell). This operationally defined distinction between axon and dendrite was verified to be nearly 90% specific in pilot experiments in which labeled processes were stained with anti-Tau antibodies to distinguish axons from dendrites. As discussed above, 74% of excitatory synapses in transfected neurons had clear surface myc-Narp stain, indicating that Narp is targeted to the synapse from the postsynaptic neuron. H...

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Abstract

A method is provided for identifying a compound which affects the formation of AMPA receptors into aggregates. A method is also provided for identifying a compound which affects the formation of synaptic connections. A method is provided for identifying a compound that modulates immediate early gene expression. A method is further provided for increasing the number of excretory synapses of a neuron, including introducing into the neuron a polynucleotide sequence encoding a Narp operatively linked to a promoter, or a Narp polypeptide, thereby increasing the number of excretory synapses of the neuron. A method is provided for treating a subject with a disorder associated with a decrease in a function or expression of Narp, including administering to the subject a therapeutically effective amount of a compound that augments Narp function or expression. A method is provided for treating a subject with a disorder associated with an increase in a function or expression of Narp, including administering to the subject a therapeutically effective of a compound that inhibits Narp function or expression. A method is provided for treating a patient having or at risk of having a disorder associated with decreased Narp expression. The method includes introducing into a cell of a patient having a disorder associated with decreased Narp expression or function a polynucleotide sequence encoding a Narp polypeptide operatively linked to a promoter. A method is provided for treating a subject having a deficiency in a neuron's immediate early gene responsiveness to a stimulus. The method includes administering a nucleic acid encoding a Narp polypeptide to said subject, wherein the administration results in amelioration of the deficiency.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation application of U.S. application Ser. No. 10 / 299,957 filed Nov. 18, 2002, now issued as U.S. Pat. No. 7,217,525; which is a continuation application of U.S. application Ser. No. 09 / 328,710 filed Jun. 9, 1999, now abandoned. The disclosure of each of the prior applications is considered part of and is incorporated by reference in the disclosure of this application.GRANT INFORMATION[0002]This invention was made with Government support under Grant No. K08NS01652, R01NS36715, R01MH53608, and K02MH01152, awarded by the National Institutes of Health. The government may have certain rights in the invention.BACKGROUND OF THE INVENTION[0003]1. Field of the Invention[0004]The present invention relates generally to molecules involved in synaptogenesis, and more specifically to the role of Narp in the formation of synapses and the clustering of receptors in synapses.[0005]2. Background Information[0006]The mature cen...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12Q1/68C12Q1/02G01N33/94
CPCG01N2510/00G01N33/9406
Inventor WORLEY, PAULO'BRIEN, RICHARDXU, DESHENGHUGANIR, RICHARD L.
Owner THE JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE
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