@Memantine a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system - too little activation is bad, too much is even worse (Parsons et al. 2007)

2022-03-04: Ionotropic Glutamate Receptor, Memantine reference:

@Memantine a: NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system - too little activation is bad, too much is even worse (Parsons et al. 2007) #

A great primer on Glutamatergic/NMDA neurotoxicity.

• AMPA is characterized by very fast activation/inactivation (milliseconds) kinetics and is mostly postsynaptic and impermeable to Ca2+.

  • Na+ flux to AMPARs induces depolarization, which removes Mg2+ blockage of NMDA, by which Ca2+/Na+ enters.
  • Ca2+-permeable AMPAR do technically exist though.

• NMDA is characterized by activation only in certain conditions i.e. during plasticity and slower gating kinetics (hundreds of milliseconds).

• Central to the hypothesis of glutamate-mediated Excitotoxicity in the pathogenesis of Alzheimer’s is that glutamate receptors, in particular of the NMDA type, are overactivated in a tonic rather than a phasic manner - this continuous mild activation leading to neuronal damage/death.

  • See the breakdown on the Ionotropic Glutamate Receptor page… besides the obvious, this can happen due to partial depolarzation via impaired Ca2+ homeostasis (maybe too much?) or too weak of an Mg2+ blockade, decreased Na+K+ ATPase activity, decrease in glucose metabolism/supply/mitochondrial dysfunction, etc.
    • Even chronic oral administration of Magnesium does not produce elevated concentrations either in plasma, red blood cells or in brain. It could even be contraindicated for ND: Magnesium triggers pathological deposition of Tau-paired helical filaments and the formation of neurofibrillary tangles. and may even cause inhibition of ACh release/muscarinic responses.

• Impairment of plasticity/learning may result not only from this damage but directly from this tonic activation alone. Phasic NMDAR activation (ie in CA1) is necessary for learning-related plasticity, but overactivation can impair it under certain conditions.

• LTP in healthy patients showed a bell-shaped dose-response curve.

• Plasticity/Learning depends on detection of relevant signal from noise/background activity, which is represented by transient, strong Ca2+ depolarization (-20mV) vs. prolonged moderate (-50mV) @ -70mV resting.

  • Is this threshold voltage they’re talking about? Thought it hd to go positive to really be a polarization

• Slow activation of presynaptic receptors on inhibitory Interneurons causes disinhibition of GABAergic synapses.

• Memantine carries only a +1 charge, compared to the obviously divalent Mg2+. There are several papers connecting disturbances of magnesium homeostasis to Alzheimer’s.
• Part 5 is a nice talk on enzyme kinetics. Low-affinity ligands/antagonists have more rapid kinetics.