Identifying and modulating molecular pathways that mediate nervous system plasticity

Abstract

The present invention provides methods for identifying genes and pathways involved in plasticity. The invention applies some of these methods to identify genes that are differentially regulated in at least a portion of the nervous system of an individual subjected to conditions known to result in altered nervous system plasticity, i.e., dark rearing (DR) or monocular deprivation (MD). The genes are targets for pharmacological agents that modify plasticity. The invention also identifies biological pathways that are enriched in genes that are differentially regulated under conditions known to result in altered nervous system plasticity. The present invention further provides methods and compositions for modifying plasticity in the nervous system of a subject. The invention includes a method for modifying plasticity in the nervous system of a subject comprising administering a plasticity-modifying agent to the subject, wherein the plasticity-enhancing agent modulates a gene or pathway that is differentially regulated in developmental conditions that alter nervous system plasticity (e.g., DR or MD). The methods and compositions may be administered to a subject suffering from damage to the nervous system or from a neuropsychiatric disorder in order to enhance recovery, reorganization, or function of the nervous system. The methods optionally include administering a proteolysis-enhancing agent to the subject.

1 . A method for modifying plasticity or aiding restoration of function in the nervous system of a subject comprising the step of:
 administering a plasticity-modifying agent to a subject in need thereof, wherein the agent is administered either alone or in combination with one or more additional agents in an amount effective to modify nervous system plasticity, wherein the plasticity-modifying agent modulates a gene or pathway that is differentially regulated in at least a portion of the nervous system of an individual subjected to a plasticity-modifying condition.   
     
     
         2 . The method of  claim 1 , wherein the condition is a neurodevelopmental disorder. 
     
     
         3 . The method of  claim 2 , wherein the neurodevelopmental disorder is selected from the group consisting of autism, Rett Syndrome, Fragile X syndrome, tuberous sclerosis, or autism spectrum disorder. 
     
     
         4 . The method of  claim 1 , wherein the condition is a neuropsychiatric disorder. 
     
     
         5 . The method of  claim 3 , wherein the neuropsychiatric disorder is selected from the group consisting of schizophrenia and bipolar disorder. 
     
     
         6 . The method of  claim 1 , wherein the condition is trauma to the nervous system caused by a condition such as stroke. 
     
     
         7 . The method of  claim 1 , wherein the plasticity-modifying condition comprises dark rearing (DR) or monocular deprivation (MD). 
     
     
         8 . The method of  claim 1 , wherein the plasticity-modifying agent is IGF1 or a modulator of the IGF1 pathway. 
     
     
         9 . The method of  claim 1 , wherein the plasticity-modifying agent is a modulator of the JAK/STAT pathway. 
     
     
         10 . The method of  claim 1 , wherein the plasticity-modifying agent is IFNγ. 
     
     
         11 . The method of  claim 1 , wherein the plasticity-modifying agent is a statin. 
     
     
         12 . The method of  claim 1 , which comprises administering a first agent that activates the IGF1 pathway and a second agent that activates the JAK/STAT pathway. 
     
     
         13 . The method of  claim 1 , wherein the plasticity-modifying agent inhibits development, survival, or activity of parvalbumin expressing interneurons. 
     
     
         14 . The method of  claim 1 , wherein the plasticity-modifying agent inhibits expression or activity of parvalbumin. 
     
     
         15 . The method of  claim 1 , wherein the plasticity-modifying agent is delivered in an amount effective to enhance the capacity of the nervous system, or a portion thereof, to restore lost function in an activity-dependent manner or in response to a second agent. 
     
     
         16 . The method of  claim 1 , wherein the plasticity-modifying agent is administered to a subject who has suffered damage to the nervous system or has been diagnosed with a disorder of the nervous system, and is administered in an amount and for a time effective to promote nervous system recovery, reorganization, or function. 
     
     
         17 . The method of  claim 1 , wherein the step of administering comprises steps of:
 (1) administering a first plasticity-modifying agent to a subject following an event that damages the brain or spinal cord or following diagnosis of a neuropsychiatric or neurodevelopmental disorder for a first period of time;   (2) administering a second plasticity-modifying agent to the subject for a second period of time, wherein the second period of time is separate from the first period of time.   
     
     
         18 - 66 . (canceled) 
     
     
         67 . A method for promoting recovery or reorganization in the nervous system of a subject comprising the step of:
 administering a plasticity-modifying agent to a subject in need thereof, wherein the agent is administered either alone or in combination with one or more additional agents in an amount effective to promote recovery or reorganization in the nervous system, wherein the plasticity-modifying agent modulates a gene or pathway that is differentially regulated in at least a portion of the nervous system of an individual subjected to a plasticity-modifying condition.   
     
     
         68 - 77 . (canceled) 
     
     
         78 . A method for promoting recovery or reorganization in the nervous system of a subject in need thereof comprising the step of:
 administering to the subject a proteolysis-enhancing agent and an agent selected from the group consisting of: agents that activate the IGF1 pathway, agents that activate the JAKISTAT pathway, agents that inhibit the development, survival, or activity of parvalbumin expressing interneurons, and agents that inhibit the expression of parvalbumin, wherein the proteolysis-enhancing agent is administered at least 3, 6, 12, 24, or more hours after a specific damaging event or diagnosis of a disorder and optionally also prior to 3 hours after the specific damaging event or diagnosis of a disorder.   
     
     
         79 . A drug delivery device for implantation into the nervous system of a subject, the drug delivery device comprising:
 a biocompatible polymer; and   a plasticity-modifying agent, wherein the plasticity-modifying agent is released from the polymer in an amount effective to modify plasticity in the nervous system of the subject.   
     
     
         80 - 101 . (canceled)