Signal-to-Noise Hypothesis

Physiological condition

NMDA receptors are transiently activated by mM concentrations of glutamate (Clements et al., 1992). In order to prevent excessive influx, the ion channel is blocked by a magnesium under resting conditions. If the NMDA receptor is activated by glutamate and the postsynaptic neuron is depolarized at the same time, magnesium leaves the ion channel and calcium can flow in, which is important for learning processes.

Figure 3a: Under normal conditions, learning is based on detection of a relevant (sufficiently strong) signal over baseline activity (here referring to Ca²⁺ fluctuations) i.e. sufficient signal-to-noise ratio.

Pathological condition

During pathological activation such as that occurring in Alzheimer’s Disease, NMDA receptors are likely activated by lower concentrations of glutamate but more or less continuously. Under such conditions, temporally uncoordinated, continuous stimulation of NMDA receptors leads to an increased calcium influx, which produces enhanced noise. The probability of detecting the relevant signal once it arrives, is decreased. This produces a progressive deficit in cognitive functions. Mg²⁺ which normally acts as a filter or switch is too weak to serve this role and the NMDA receptor can no longer function as a coincidence detector. This overactivation of glutamate receptors and continuous Ca²⁺ influx ultimately leads to damage of neurones not able to compensate and further decline of cognitive functions. This mechanism (overactive glutamatergic synapses) may be responsible for both cognitive deficits and neuronal loss in neurodegenerative dementia.

Figure 3b: Our signal-to-noise ratio hypothesis assumes that in Alzheimer’s disease, due to overactive glutamatergic system, Mg²⁺ is not effective enough to play its “filtering” function. In turn, synaptic noise rises, impairing detection of the relevant signal such as in learning.

Search for a better magnesium

A more effective surrogate for Mg²⁺ ions would be required to counteract this deficit. Mg²⁺, the endogenous antagonist of NMDA receptors, is necessary for normal function, and obviously “well tolerated” in contrast to high affinity antagonists such dizocilpine – (+)MK-801) which produce numerous side effects.

What makes these antagonists so different even though both act at the same channel site of the NMDA receptor?

Electrophysiological experiments showed that affinity, kinetics and voltage-dependency are crucial determinants of tolerability.

• Mg²⁺ shows strong voltage-dependency and very low affinity which is associated with fast blocking kinetics.
• Dizocilpine shows very high affinity which is associated with very slow kinetics and weak voltage-dependency.
• Electrophysiological studies revealed that the moderate potency of memantine is associated with kinetics and voltage-dependency between those of Mg²⁺ and dizocilpine.

NMDA-Protection with memantine

As a result of its less pronounced voltage-dependency, memantine is more effective than Mg²⁺ in blocking pathological activation of NMDA receptors. However, following strong synaptic activation, memantine like Mg²⁺, can leave the NMDA receptor channel due to its voltage-dependency and fast unblocking kinetics. Memantine suppresses synaptic noise but allows the relevant physiological synaptic signal to be detected. This provides both neuroprotection and symptomatic restoration of synaptic plasticity by one and the same mechanism.

Figure 3c: Scheme explaining memantine’s action in Alzheimer’s disease based on the signal-to-noise hypothesis. Memantine is able to serve as a filter blocking “synaptic noise” and thereby allowing detection of the relevant signal i.e. synaptic plasticity is restored. Modified with permission from (Danysz et al., 2000). Copyrights belong to Taylor & Francis Limited.