REVIEW Developing a Neuronal Model for the Pathophysiology of Schizophrenia Based on the Nature of Electrophysiological Actions of Dopamine in the Prefrontal Cortex Charles R. Yang, Ph.D., Jeremy K. Seamans, Ph.D., and Natalia Gorelova, Ph.D. This review covers some recent findings of the same schizophrenic patient in the course of the illness. We electrophysiological mechanisms through which hypothesize that the dysfunctional mesocortical dopamine mesocortical dopamine modulates prefrontal cortical input to the PFC may lead to abnormal modulation of neurons. Dopamine has been shown to modulate several ionic channels distributed in the dendritic–somatic ionic conductances located along the soma-dendritic axis of compartments of PFC pyramidal neurons that project to the prefrontal cortical pyramidal neurons. These ionic currents ventral tegmental area and/or nucleus accumbens. In some include high-voltage-activated calcium currents and slowly schizophrenics, a reduction of mesocortical dopamine to inactivating Na1 and K1 currents. They contribute actively below optimal levels and/or a loss of local GABAergic in processing functionally segregated inputs during inputs may result in a dysfunctional integration of extrinsic synaptic integration. In addition, dopamine mainly associative inputs by Ca21 channel activity in the distal depolarizes the fast-spiking subtype of local GABAergic dendrites of PFC pyramidal neurons. This may account for interneurons that connect the pyramidal neurons. This the patients’ distractibility caused by their inability to focus latter action can indirectly control pyramidal cell only on relevant external inputs. In contrast, in acute stress excitability. These electrophysiological data indicate that the or psychotic episodes, an associated abnormal elevation of actions of dopamine are neither “excitatory” nor mesocortical dopamine transmission may greatly influence “inhibitory” in pyramidal prefrontal cortex neurons. distal dendritic Ca21 channel-mediated signal-processing Rather, the actions of dopamine are dependent on soma- mechanisms. This can enhance possible reverberative dendritic loci, timing of the arrival of synaptic inputs, activity between adjacent interconnected pyramidal strength of synaptic inputs, as well as the membrane neurons via the effects of dopamine on the slowly potential range at which the PFC neuron is operating at a inactivating Na1, K1, and soma-dendritic Ca21 currents. given moment. Based on available electrophysiological The effects of high levels of PFC dopamine in this case may findings, a neuronal model of the pathophysiology of contribute to behavioral perseveration and stereotypy so schizophrenia is presented. This model proposes that that the patients are unable to use new external cues to episodic hypo- and hyperactivity of the PFC and the modify ongoing behaviors. [Neuropsychopharmacology associated dysfunctional mesocortical dopamine system 21:161–194, 1999] © 1999 American College of (and their interconnected brain regions) may coexist in the Neuropsychopharmacology. Published by Elsevier Science Inc. From the Neuroscience Research (CRY), DC 0510, Eli Lilly & Address correspondence to: C. Y. Yang, Ph.D., Eli Lilly and Com- Company, Lilly Corporate Center, Indianapolis, Indiana; Depart- pany, Neuroscience Research, DC 0510, Lilly Corporate Center, ment of Psychology and Psychiatry (CRY, NG), University of British Indianapolis, IN 46285. Columbia, Vancouver, BC, Canada; and Computational Neurobiol- Received May 12, 1998; revised May 27, 1998; accepted May 29, ogy Lab (JKS), The Salk Institute, La Jolla, California. 1998. NEUROPSYCHOPHARMACOLOGY 1999–VOL. 21, NO. 2 © 1999 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/99/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(98)00112-2 162 C.R. Yang et al. NEUROPSYCHOPHARMACOLOGY 1999–VOL. 21, NO. 2 1 KEY WORDS: Dopamine; Schizophrenia; Dendrites; Ca2 Channels; Persistant sodium current; Prefrontal cortex; Nuclues accumbens, GABA interneuron Schizophrenia strikes one in one hundred people worldwide, regardless of cultural or racial origins. As the illness progresses and if it remains unattended, pa- tients are frequently trapped in psychological, social, and economic devastation (Gottesman 1991; Jablensky 1995). Currently, our incomplete understanding of the neurobiological bases of schizophrenia suggests that defects in the genetic controls of brain development in such limbic regions (including temporal lobe structures such as hippocampus and the amygdala) as well as the prefrontal cortex (PFC) lead to cell loss or deformation, cytoarchitectural disorganization, and abnormal inner- vation in these brain regions (Roberts and Bruton 1990; Stevens 1992; Bogerts 1993; Shapiro 1993; Akbarian et al. 1993, 1996; Ross and Pearlson 1996; Weinberger 1996; Karayiorgou and Gogos 1997; Lewis 1997; Selemon et al. 1995, 1998). Some results from recent imaging studies of brains from living schizophrenics have suggested that there are defective functional communications between the interconnected cortical (PFC and cingulate cortex) and limbic subcortical structures (thalamus, striatum, and temporal lobe limbic structures)(see reviews of Liddle Figure 1. Schematic drawing illustrating the neuroanatom- 1996; Pfefferbaum and Marsh 1995; Andreasen 1997; ical interrelationship between amygdala, hippocampus PFC Heckers et al. 1998). Findings from these studies sug- and Nac, as well as PFC outputs to the NAc, and the A10 gest that in schizophrenics, abnormal recruitment of dopamine perikarya in the VTA. These connections provide several interconnected cortical and subcortical struc- the potential functional links by which cortical and subcorti- tures may underlie such symptom clusters as psycho- cal dopamine systems may interact. motor poverty, thought disorganization, and reality distortion (Liddle et al. 1992; Liddle 1996; Fletcher 1998; Heckers et al. 1998). lines of evidence seem to favor this hypothesis. First, As noted in Figure 1, the PFC receives converging many clinically efficacious antipsychotics are potent limbic, association cortical, and mesocortical dopamine dopamine receptor antagonists (Seeman 1992). Second, inputs. These inputs interact in the PFC and are in- dopamine receptors (Okubo et al. 1997) or the release volved functionally in high-level cognitive processes dynamics of dopamine terminals (Wong et al. 1997) are (Fuster 1995). Among the many brain regions that PFC markedly altered in living schizophrenic brains. Third, output innervates, two important subcortical regions several psychoactive substances (e.g., amphetamine, are emphasized in this review. These are the nucleus ac- phencyclidine) abnormally augment dopamine trans- cumbens (where mesoaccumbens dopamine neurons mission and induce psychotic symptoms indistinguish- terminate) and the ventral tegmental area (VTA, where able from schizophrenia. These lines of evidence have the midbrain dopamine neurons reside) (Sesack et al. provided the bases for the “Dopamine Hypothesis of 1989; Groenewegen et al. 1990; Berendse et al. 1992a, Schizophrenia” (Davis et al. 1991; Cohen and Servan- 1992b; Sesack and Pickel 1992; Gorelova and Yang Schreiber 1993; Carlson 1995). 1997b). Several of the interconnected limbic, cortical, Detailed electrophysiological mechanisms that un- and subcortical structures known to be affected in derlie the dynamic actions of neurons (i.e., in the time- schizophrenia are targets of the ascending midbrain scale of milliseconds, seconds, to minutes) in inter- dopamine systems that normally provide functional connected cortical-subcortical network of neurons are modulation of neurotransmission (Björklund and Lind- currently lacking. This review focuses primarily on the vall 1984; Mogenson et al. 1993). nature of electrophysiological actions of dopamine in Alteration of dopamine transmission in PFC and/or the PFC. It is hoped that an understanding of dopami- the nucleus accumbens has been hypothesized to be nergic actions on cortical–subcortical interactions may part of the pathophysiology of schizophrenia. Several lead to some insights into the mechanisms responsible NEUROPSYCHOPHARMACOLOGY 1999–VOL. 21, NO. 2 Prefrontal Dopamine Electrophysiology and Schizophrenia 163 for the dopamine-mediated pathophysiology of schizo- much more expanded area of innervation in primate and phrenia. Based on available electrophysiological results, human cortices, encompassing a widespread area of the we attempt to provide a neuronal model to account for sensorimotor and association cortices. In primate and certain aspects of the pathophysiology of schizophrenia. human brain, a substantial amount of tyrosine hydrox- Although outside the scope of this review, we acknowl- ylase- or dopamine-immunoreactive fibers are found in edge that other neurotransmitter/neuromodulator sys- the motor, premotor, supplementary motor area, pari- tems undoubtedly interact with the dopamine systems etal, temporal, and posterior cingulate cortices (sen- to contribute to the complex pathophysiology of schizo- sorimotor), in addition to prefrontal, anterior cingulate, phrenia. Among the neurotransmitter systems impli- insular, piriform, perirhinal, and entorhinal cortices (as- cated are those that use glutamate (Olney and Farber sociation)(Berger et al. 1988; Gaspar et al. 1989; Smiley 1995), serotonin (Iqbal and van Praag 1995; Kapur and and Goldman-Rakic 1993). Remington 1996; Busatto and Kerwin 1997; Marek