The neuroanatomy of schizophrenia: circuitry and neurotransmitter systems

Abstract This paper explores the basis of schizophrenia from a neuroanatomical systems perspective. This perspective includes an analysis of the literature on the neurochemical, neurotransmitter, morphological, neurophysiological, connectional, developmental, neurosurgical, behavioral, neurological, and psychophysical aspects of schizophrenia. The convergence of evidence from these diverse subfields of inquiry are then mapped as interacting circuits throughout the neuraxis. Viewed from these specific and whole brain points of view, several patterns emerge. First, virtually all major brain areas and circuits in the brain have been implicated in the etiology and symptomotology of schizophrenia. This is consistent with the multiple forms of schizophrenia and the constellation of clinical syndromes associated with the different schizophrenias. Second, although numerous, widely dispersed circuits are implicated, all circuits directly impact connections and functions of the dorsal prefrontal cortex, and specifically the cortico-cortical and corticosubcortical pyramidal neuron outputs and loop systems back to these pyramidal neurons. The neuronal systems most intimately associated with regulation of pyramidal neuron function are local GABA-ergic interneuronal inputs, dopaminergic inputs, glutaminergic drive, and differential regulation of excitability and firing of these neurons by the segregated inputs and local receptor and channel properties of the distal vs proximal compartments of the pyramidal neurons. The dorsal and dorsolateral prefrontal cortex appears to be at particular risk to dysregulated inputs, whereas the orbital cortex appears to more protected from hypofunctionality, perhaps due, in part, from a richer array of cortico-cortical inputs, and a relative independence from cerebellar dysmetric influences. Other cortical areas of the temporal lobe are, to a lesser degree, influential in the primary neuronal dysfunctioning in schizophrenia. Thus, although many brain circuits and neurotransmitter systems are implicated in schizophrenia, their ultimate impact on the dorsal prefrontal cortex pyramidal neuron, appear to be the common cause in this disease.