Figure 1.

Schematic and simplified representation of CSMN modulation by local neuronal circuitries and long-range projection neurons in normal physiological conditions and in disease. (A) Thalamocortical projections provide excitatory input to CSMN. The site of neuronal modulation is suggested to be mainly within layer II/III and layer V. CSMN are also heavily modulated by both ipsi and contralateral callosal projection neurons that are mainly located within layer II/III and layer V of the cerebral cortex. Local circuitry neurons also modulate CSMN activity either directly or via an interneuron. In particular, LTS (low-threshold-spiking) and FS (fast-spiking) interneurons are differentially involved in the inhibitory microcircuit. While LTS interneurons receive interlaminar input from layer II/III projection neurons, FS receive intralaminar input from CSMN illustrating a possible distinct mechanism for disynaptic CSMN inhibition. Excitatory inputs impinge mainly upon the spines that are located on the dendrites located in layer II/III and layer V, and inhibitory input is conveyed mainly on the spines that are directly located on the apical dendrite and on a subset of spines that are present on basal dendrites. (B) In ALS, CSMN show vulnerability and undergo progressive degeneration. At pre-symptomatic stage (i.e., P60) CSMN display major spine loss within apical, but not basal, dendrites and apical dendrites undergo massive vacuolation and lose cytoarchitectural integrity. Such cellular defects would have profound impact on CSMN modulation. How circuitries are affected in disease require further investigation. Excitatory and inhibitory input is denoted by lines and dashed lines, respectively.