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.