Protein synthesis required for long-term memory is induced by pkc activation on days preceding associative learning

Abstract

The present invention provides methods of contacting a protein kinase C (PKC) activator with a PKC activator in a manner sufficient to stimulate the synthesis of proteins sufficient to consolidate long-term memory. The present invention also provides methods of contacting a protein kinase C (PKC) activator with a PKC activator in a manner sufficient to downregulate PKC.

1 . A method comprising the step of contacting a PKC activator with a protein kinase C (PKC) to stimulate the synthesis of proteins sufficient to consolidate long term memory. 
     
     
         2 . The method of  claim 1 , wherein said PKC activator is a macrocyclic lactone. 
     
     
         3 . The method of  claim 1 , wherein the PKC activator is a benzolactam. 
     
     
         4 . The method of  claim 1 , wherein the PKC activator is a pyrrolidinone. 
     
     
         5 . The method of  claim 2 , wherein the macrocyclic lactone is a bryostatin. 
     
     
         6 . The method of  claim 5 , wherein the bryostatin is bryostatin-1, -2, -3, -4, -5, -6, -7, -8, -9, -10, -11, -12, -13, -14, -15, -16, -17, or -18. 
     
     
         7 . The method of  claim 5 , wherein the bryostatin is bryostatin-1. 
     
     
         8 . The method of  claim 2 , wherein the macrocyclic lactone is a neristatin. 
     
     
         9 . The composition of  claim 8 , wherein the neristatin is neristatin-1. 
     
     
         10 . The method of  claim 1 , wherein said contact activates PKC. 
     
     
         11 . The method of  claim 1 , wherein said contact increases the amount of PKC. 
     
     
         12 . The method of  claim 1 , wherein said contact increases the synthesis of PKC. 
     
     
         13 . The method of  claim 1 , wherein said contact increases the amount of calexcitin. 
     
     
         14 . The method of  claim 1 , wherein said contact does not result in substantial subsequent downregulation of PKC. 
     
     
         15 . The method of  claim 1 , wherein the contacting of the PKC activator with the PKC is repeated. 
     
     
         16 . The method of  claim 15 , wherein the contacting of the PKC activator with the PKC is repeated at regular intervals. 
     
     
         17 . The method of  claim 16 , wherein the interval is between one week to one month, one day and one week, or less than one hour and 24 hours. 
     
     
         18 . The method of  claim 17 , wherein the interval is between one week and one month. 
     
     
         19 . The method of  claim 17 , wherein the interval is between one day and one week. 
     
     
         20 . The method of  claim 17 , wherein the interval is between less than one hour and 24 hours. 
     
     
         21 . The method of  claim 1 , wherein the contacting of the PKC activator with the PKC is maintained for a fixed duration. 
     
     
         22 . The method of  claim 21 , wherein the fixed duration is less than 24 hours. 
     
     
         23 . The method of  claim 21 , wherein the fixed duration is less than 12 hours. 
     
     
         24 . The method of  claim 21 , wherein the fixed duration is less than 6 hours. 
     
     
         25 . The method of  claim 21 , wherein the fixed duration is less than 4 hours. 
     
     
         26 . The method of  claim 21 , wherein the fixed duration is less than 2 hours. 
     
     
         27 . The method of  claim 21 , wherein the fixed duration is between about 2 and about 6 hours. 
     
     
         28 . The method of  claim 21 , wherein the fixed duration is about 4 hours. 
     
     
         29 . The method of  claim 21 , wherein said duration of said contact is between about 1 and about 12 hours. 
     
     
         30 . The method of  claim 15 , wherein said contact is repeated for a period greater than one day. 
     
     
         31 . The method of  claim 15 , wherein said contact is repeated for a period between one day and one month. 
     
     
         32 . The method of  claim 15 , wherein said contact is repeated for a period between one day and one week. 
     
     
         33 . The method of  claim 15 , wherein said contact is repeated for a period between one week and one month. 
     
     
         34 . The method of  claim 15 , wherein said contact is repeated for a period between one month and six months. 
     
     
         35 . The method of  claim 15 , wherein said contact is repeated for a period of one month. 
     
     
         36 . The method of  claim 15 , wherein said contact is repeated for a period greater than one month. 
     
     
         37 . A method comprising the step of contacting a PKC activator with a protein kinase C (PKC) to downregulate PKC. 
     
     
         38 . The method of  claim 37 , wherein said PKC activator is a macrocyclic lactone. 
     
     
         39 . The method of  claim 37 , wherein the PKC activator is a benzolactam. 
     
     
         40 . The method of  claim 37 , wherein the PKC activator is a pyrrolidinone. 
     
     
         41 . The method of  claim 38 , wherein the macrocyclic lactone is a bryostatin. 
     
     
         42 . The method of  claim 41 , wherein the bryostatin is bryostatin-1, -2, -3, -4, -5, -6, -7, -8, -9, -10, -11, -12, -13, -14, -15, -16, -17, or -18. 
     
     
         43 . The method of  claim 42 , wherein the bryostatin is bryostatin-1. 
     
     
         44 . The method of  claim 38 , wherein the macrocyclic lactone is a neristatin. 
     
     
         45 . The composition of  claim 38 , wherein the neristatin is neristatin-1. 
     
     
         46 . The method of  claim 37 , wherein said contact produces downregulation of PKC. 
     
     
         47 . The method of  claim 46 , wherein said contact produces substantial downregulation of PKC. 
     
     
         48 . The method of  claim 37 , wherein said contact does not stimulate the synthesis of PKC. 
     
     
         49 . The method of  claim 48 , wherein said contact does not substantially stimulate the synthesis of PKC. 
     
     
         50 . The method of  claim 37 , wherein said contact decreases the amount of PKC. 
     
     
         51 . The method of  claim 50 , wherein said contact substantially decreases the amount of PKC. 
     
     
         52 . The method of  claim 37 , wherein said contact does not stimulate the synthesis of calexcitin. 
     
     
         53 . The method of  claim 50 , wherein said contact does not stimulate the synthesis of calexitin. 
     
     
         54 . The method of  claim 37 , wherein the contacting of the PKC activator with the PKC is for a sustained period. 
     
     
         55 . The method of  claim 54 , wherein the sustained period is between less than one hour and 24 hours. 
     
     
         56 . The method of  claim 54 , wherein the sustained period is between one day and one week. 
     
     
         57 . The method of  claim 54 , wherein the sustained period is between one week and one month. 
     
     
         58 . The method of  claim 54 , wherein the sustained period is between less than one hour and 12 hours. 
     
     
         59 . The method of  claim 54 , wherein the sustained period is between less than one hour and 8 hours. 
     
     
         60 . The method of  claim 54 , wherein the sustained period is between less than one hour and 4 hours. 
     
     
         61 . The method of  claim 54 , wherein the sustained period is about 4 hours. 
     
     
         62 . The method of  claim 37 , wherein said contact produces sustained downregulation of PKC. 
     
     
         63 . The method of  claim 1 , further comprising the step of inhibiting degradation of protein kinase C (PKC). 
     
     
         64 . The method of  claim 63 , wherein said degradation is through ubiquitination. 
     
     
         65 . The method of  claim 64 , wherein said degradation is inhibited by lactacysteine. 
     
     
         66 . The method of  claim 1 , wherein the PKC is human. 
     
     
         67 . The method of  claim 1 , wherein the PKC activator is provided in the form of a pharmaceutical composition comprising the PKC activator and a pharmaceutically acceptable carrier. 
     
     
         68 . The method of  claim 67 , wherein the pharmaceutical composition further comprises a PKC inhibitor. 
     
     
         69 . The method of  claim 68 , wherein the PKC inhibitor inhibits PKC in peripheral tissues. 
     
     
         70 . The method of  claim 68 , wherein the PKC inhibitor selectively inhibits PKC in peripheral tissues. 
     
     
         71 . The method of  claim 68 , wherein the PKC inhibitor is a compound that reduces myalgia associated with the administration of a PKC to a subjects. 
     
     
         72 . The method of  claim 68 , wherein the PKC inhibitor is a compound that increases the tolerable dose of a PKC activator. 
     
     
         73 . The method of  claim 68 , wherein the PKC inhibitor is vitamin E, vitamin E analogs, vitamin E salts, calphostin C, thiazolidinediones, ruboxistaurin or combinations thereof.