Methods of Modifying Neuronal Function by Changing Intracellular Magnesium Levels

Abstract

Methods for modifying neuronal functional activity and/or treating a neurological disorder by using agents that raise neuronal intracellular concentration of magnesium are disclosed. Also provided herein are methods of determining the amenability of an individual to treatment for a neurological disorder, by measuring changes in intracellular magnesium concentration.

1 . A method of modifying a functional property of neurons, comprising contacting one or more neurons comprising a presynaptic terminal, with a composition comprising an effective amount of an intracellular magnesium concentration ([Mg 2+ ] i )-elevating agent, to modify one or more functional properties of the neurons,
 wherein the functional property comprises one or more of:
 a functional presynaptic terminal density; 
 a mitochondrial function per unit dendritic area; 
 a terminal abundance of one or more presynaptic Ca 2+  sensitivity-related proteins; and 
 a probability of synaptic release in response to low frequency single action potential input. 
   
     
     
         2 . The method of  claim 1 , wherein the contacting:
 increases the functional presynaptic terminal density;   increases the mitochondrial function per unit dendritic area;   increases the abundance of one or more presynaptic Ca 2+  sensitivity-related proteins; and/or   reduces the probability of synaptic release.   
     
     
         3 . The method of  claim 1 , wherein the [Mg 2+ ] i -elevating agent comprises a magnesium-containing compound, a magnesium influx promoter or an inhibitor of intracellular magnesium efflux. 
     
     
         4 . The method of  claim 1 , wherein the effective amount of the [Mg 2+ ] i -elevating agent raises an intracellular concentration of magnesium in the one or more neurons by 1.1 fold or more. 
     
     
         5 . The method of  claim 1 , wherein the contacting comprises administering an effective amount of the [Mg 2+ ] i -elevating agent, or a precursor thereof, to an individual. 
     
     
         6 . The method of  claim 5 , wherein the [Mg 2+ ] i -elevating agent, or a precursor thereof, is administered orally. 
     
     
         7 . The method of  claim 1 , wherein the method is for treating a neurological disorder, or a symptom thereof, in the individual. 
     
     
         8 . The method of  claim 7 , wherein the neurological disorder is associated with insufficient synaptic density and/or insufficient neuron number in the individual, or is associated with sustained and/or elevated spontaneous activity of neurons in the individual. 
     
     
         9 . The method of  claim 8 , wherein the neurological disorder is selected from Alzheimer's disease, mild cognitive impairment (MCI), Parkinson's disease, dementia, Huntington's disease, autism, schizophrenia, cognitive decline as a secondary effect of disease or medical treatment, depression, sleep disorder, anxiety, attention deficit hyperactivity disorder (ADHD), migraine, headache, stroke, neuropathy, epilepsy, cerebral palsy, chronic pain, involuntary muscular contractions and convulsive twitches, spasm, wrinkling, dystonia and tremor, anxiety and depression associated with sustained neural activity in prefrontal cortex (PFC) and amygdala, and insomnia. 
     
     
         10 . A method comprising:
 administering a [Mg 2+ ] i -elevating agent to an individual having or suspected of having a neurological disorder;   determining a first level of magnesium in blood cells of a first blood sample obtained from the individual before the administering; and   evaluating a change in cognitive competency of the individual from before to after the administering.   
     
     
         11 . The method of  claim 10 , further comprising measuring the level of magnesium in the blood cells, before the administering, to determine the first level of magnesium. 
     
     
         12 . The method of  claim 10 , further comprising determining a second level of magnesium in blood cells of a second blood sample obtained from the individual after the administering. 
     
     
         13 . The method of  claim 12 , further comprising measuring the level of magnesium in the blood cells, after the administering, to determine the second level of magnesium. 
     
     
         14 . The method of  claim 12 , further comprising continuing administration of the [Mg 2+ ] i -elevating agent to the individual when the second level of magnesium is greater than the first level of magnesium. 
     
     
         15 . The method of  claim 10 , wherein the cognitive competency comprises executive function, working memory, attention and/or short-term episodic memory. 
     
     
         16 . The method of  claim 15 , further comprising administering a cognitive test for evaluating the cognitive competency of the individual before and/or after administering the [Mg 2+ ] i -elevating agent. 
     
     
         17 . The method of  claim 12 , further comprising continuing administration of the [Mg 2+ ] i -elevating agent to the individual when the cognitive competency is not improved or is substantially the same as from before to after administering the [Mg 2+ ] i -elevating agent, and when the second level of magnesium is greater than the first level of magnesium. 
     
     
         18 . The method of  claim 10 , wherein the neurological disorder comprises cognitive impairment and/or a magnesium deficiency-caused neurological disorder. 
     
     
         19 . The method of  claim 18 , wherein the cognitive impairment comprises age-related cognitive decline, mild cognitive impairment, Alzheimer's disease, or cognitive fluctuation. 
     
     
         20 . The method of  claim 10 , wherein the blood cells comprise red blood cells. 
     
     
         21 .- 29 . (canceled)