Figure 5. CStr-related changes in autism spectrum disorder (ASD), amyotrophic lateral sclerosis (ALS), and major depressive disorder (MDD).

(A) Many changes in ASD are IT-related. Changes (depicted by yellow circles) observed in human ASD include: (1) mildly increased cortical thickness, (2) abnormal interhemispheric and long-range corticocortical synchrony, resulting in a relative disconnection of IT neurons in the contralateral cortex (dashed lines), and (3) thinning of corpus callosum (gray ellipse). Changes observed in mouse models include: (4) increased excitatory synaptic connectivity (small black arrows) from layer 2/3 neurons (orange) to layer 5 IT neurons (red) but not PT neurons (blue), in Met knockout mice; (5) changes at CStr synapses in Shank3 knockout mouse, and changes in striatal neuron dendrites in Met knockout mice. There is (6) relative sparing of pyramidal system functions. (B) Many changes in ALS are PT-related. Changes (depicted by yellow circles) observed include: (1) early cortical hyperexcitability, and hyperactivity during movement; (2) degenerative changes in layer 2/3 neurons; (3) selective degeneration of corticospinal (PT) neurons, with no known pathology of IT-CStr neurons; (4) reduction in PV immunoreactivity in human ALS cortex, but an increase in PV-positive cells in the SOD1 mouse model of ALS; (5) abnormal long-term plasticity at CStr synapses. (C) IT-CStr-related changes in MDD. Changes affecting the CStr projection in MDD include abnormal activity in (1) cortex and (2) striatum in human imaging studies, and (3) IT-CStr-specific upregulation of the calcium-binding protein p11 and 5HT-4 serotonin receptors induced by chronic treatment with the antidepressant fluoxetine (FLX) ¹⁸¹.