AMPA receptor mediated excitotoxicity in ALS: pathophysiology and neuropharmacology

The term excitotoxicity was coined for the overstimulation of neurons via glutamate receptor channels. AMPA-type glutamate receptors (AMPA-R) are the most abundant excitatory transmitter receptors of the central nervous system. They play a major role in the cascade of cell damage in neurodegenerative diseases like amyotrophic lateral sclerosis. Neurons that are vulnerable to excitotoxicity express specific subtypes of AMPA-R as defined by the combination of subunits, by alternative splicing, and by nuclear editing of subunit mRNAs.

The investigation of the neurophysiological properties of specific AMPA-R allows for the detection of factors of vulnerability on the molecular level. In our studies on the expression of receptor channels in neurons in the CNS of ALS patients we combined in situ hybridization techniques with immunohistochemistry to reveal the specific receptor pattern of vulnerable neurons.

In our neurophysiological studies, we combined the characterization of AMPA-R subtypes that were recombinantely expressed with the analysis of native receptors on the single channel level, within synaptic contacts and networks in cell culture, and using brain slice techniques. The data from these studies gave a basis for the testing of compounds that are candidates for pharmacological neuroprotection.

We investigated the molecular mechanism of action of a broad variety of compounds interacting with AMPA-R (e.g. RPR119990, RPR117824, memantine, topiramate, IEM1460, ZK187638, ZK200775). The receptor channel subtype specificity of the compounds was characterized as well as the molecular mechanism of action on the single channel and on the synaptic level. The molecular drug profiles will be compared with pharmacological data from in vitro and in vivo models of neurodegeneration to develop more effective strategies for pharmacological neuroprotection.

In conclusion, antagonizing glutamatergic neurotransmission is an important therapeutic strategy in neurodegenerative diseases and requires crucially the investigation of the synaptic integration of vulnerable neurons and of

the molecular mechanisms of AMPA-R activation and modulation.

Supported by the DFG, the DGM, Sofi-Aventis, Schering