Figure 2.

A schematic illustration of putative pathological processes in schizophrenia – emphasizing the interactions among neuromodulatory mechanisms. These mechanisms include: (i) decreased prefrontal NMDA-R function that may reduce the stimulation of VTA-DA neurons that project back to prefrontal D₁Rs (decreasing cortical precision), and disinhibition of VTA-DA neurons that project to the striatum; (ii) increased dopamine release from SNc-DA neurons disinhibits the indirect pathway (by direct inhibition of striatal GABA neurons, inhibition of striatal cholinergic interneurons, and reduction of glutamate release in corticostriatal neurons); (iii) reduced NMDA-R stimulation of cortical PVBC’s reduces activity of these GABAergic interneurons, impairing coordination of cortical oscillatory activity; and (iv) increased hippocampal drive to the VTA, leading to hyperdopaminergia in the VStr. Significant omissions (for clarity) include: the GP, SNr, STN, and Thal, most connections of the VStr including its direct and indirect pathways and excitatory connections from the VTA (via D₁Rs), and circuitry within the VStr, two more inhibitory connections in the indirect pathway and both somatic and axonal dopamine neuron D₂ autoreceptors in SNc. As in other figures, descending projections are in black and ascending projections in red. Abbreviations: PPT, pedunculopontine tegmental nucleus; VTA, ventral tegmental area; VStr, ventral striatum; DStr, dorsal striatum; SNc/r, substantia nigra pars compacta/reticulata; GP, globus pallidus; Thal, thalamus; STN, subthalamic nucleus; PVBC, parvalbumin-positive basket cell. Stephan et al. (2009), Morrison (2012), Carlsson et al. (1999), Lisman et al. (2008), Simpson et al. (2010).