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Disinhibition of Prefrontal Cortex Neurons in Schizophrenia

  • B. Moghaddam
  • A.L. Pehrson
Chapter

Abstract

A large body of evidence has implicated abnormal functioning of the prefrontal cortex (PFC) in the pathophysiology of schizophrenia (Robbins 1996; Andreasen et al. 1997; Winterer and Wvneinberger 2004; Lewis and Moghaddam 2006). These abnormalities are found at molecular and functional levels and are thought to be the basis of cognitive deficits in individuals with schizophrenia. However, little is known about the physiological mechanisms that contribute to this malfunction. Here we review some of the literature that points to PFC abnormalities in schizophrenia and recent theories that unify the multimodal functional and postmortem findings in schizophrenia.

Keywords

NMDA Receptor Pyramidal Neuron Antipsychotic Drug NMDA Receptor Antagonist Glutamate Neurotransmission 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Introduction

A large body of evidence has implicated abnormal functioning of the prefrontal cortex (PFC) in the pathophysiology of schizophrenia (Robbins 1996; Andreasen et al. 1997; Winterer and Wvneinberger 2004; Lewis and Moghaddam 2006). These abnormalities are found at molecular and functional levels and are thought to be the basis of cognitive deficits in individuals with schizophrenia. However, little is known about the physiological mechanisms that contribute to this malfunction. Here we review some of the literature that points to PFC abnormalities in schizophrenia and recent theories that unify the multimodal functional and postmortem findings in schizophrenia.

Previous mechanistic investigations of the pathophysiology of schizophrenia have primarily focused on dopaminergic and cholinergic systems in different subregions of the PFC (Geraud et al. 1987; Goldman-Rakic 1987; Daniel et al. 1989, 1991; Lewis et al. 1992; McGaughy et al. 1996; Robbins 1998). This has been justified by the fact that well-known antipsychotic drugs are thought to exert their therapeutic actions by blocking the dopamine D2 receptors. Furthermore, manipulation of dopamine receptors in the PFC profoundly affects cognitive functions such as working memory that are dependent on the functional integrity of the PFC (Goldman-Rakic 1987) and disrupted in schizophrenia (Keefe 2001). More recent work has shifted the attention to glutamate and GABA-containing neurons. The glutamatergic afferents to the PFC originate primarily in regions that have been implicated in the etiology and pathophysiology of schizophrenia such as the thalamus, amygdala, and the hippocampus (Jeste and Lohr 1989; Conrad et al. 1991; Harrison et al. 1991; Andreasen et al. 1994, 1999). Dysfunctional glutamate neurotransmission, in particular NMDA receptor-mediated neurotransmission, has been linked to schizophrenia (Kim et al. 1980; Javitt and Zukin 1991; Olney and Farber 1995) primarily because noncompetitive NMDA receptor antagonists such as phencyclidine (PCP) and ketamine are psychotomimetic and produce, in healthy individuals, behaviors that resemble the cognitive deficits (Krystal et al. 1994; Malhotra et al. 1996; Adler et al. 1998) and some of the negative and positive symptoms of schizophrenia (Luby et al. 1959; Javitt and Zukin 1991; Krystal et al. 1994). GABA neurons are the most prevalent interneurons in the PFC and are thought to tightly control the activity of PFC afferents (Aradi et al. 2002). Recent studies link schizophrenia to increased GABAA expression on pyramidal neurons (Benes et al. 1996), reduced expression of the GABA reuptake transporter GAT1 (Woo et al. 1998; Pierri et al. 1999), and reductions in the GABA-synthesizing enzyme GAD67 (Akbarian et al. 1995; Volk et al. 2000), suggesting that GABA-mediated inhibitory neurotransmission in the cortex may be disrupted.

Dopamine Dysfunction in Schizophrenia

Altered dopamine neurotransmission has been a suspected cause in some features of schizophrenia for some time and has led to the influential dopamine hypothesis of schizophrenia (Carlsson 1977). This is based largely on observations that dopamine agonists such as amphetamine induce symptoms of psychosis (Randrup and Munkvad 1965), while dopaminergic D2 receptor antagonists attenuate these symptoms. Indeed, there is a strong correlation between the clinical potency of many antipsychotics and their affinity for the D2 receptor (Seeman and Lee 1975; Creese et al. 1976) and striatal D2 receptor occupancy between 60 and 70% predicts clinical response to first-generation antipsychotics such as haloperidol (Kapur et al. 2000; Farde et al. 1988). Further support for altered dopamine neurotransmission in schizophrenia comes from observations that patients with this disease have significantly greater increases in dopamine release than controls under baseline conditions (Abi-Dargham et al. 2000) and in response to acute amphetamine challenge (Breier et al. 1997; Laruelle et al. 1996; Abi-Dargham et al. 1998). Furthermore, a recent meta-analysis reports a small but significant increase in striatal D2 receptors in patients with schizophrenia (Weinberger and Laruelle 2001). A plausible interpretation of data such as these is that schizophrenia is related to hyperactive dopamine neurotransmission, particularly in the striatum.

But there is also evidence that calls the relationship between hyperactive striatal dopamine and psychotic symptoms into question. For example, although schizophrenia appears to be related to increased basal dopamine release and D2 receptor density in the striatum, the magnitude of these changes has not been correlated with the severity of the positive symptom cluster (Abi-Dargham et al. 2000; Weinberger and Laruelle 2001). Furthermore, the idea that an overactive dopamine system elicits symptoms of schizophrenia is not supported by the fact that dopamine D1 antagonists have not been found to have antipsychotic efficacy. Blocking D1 receptors is generally more effective than D2 receptors in ameliorating behavioral effects of hyperdopaminergic states in laboratory animals (Arnsten et al. 1994; Cuomo et al. 1986; Kuczenski and Segal 1999). Therefore, symptoms resulting from a hyperactive dopamine system should be more effectively reversed by a D1 antagonist than a D2 antagonist, which is not the case in schizophrenia. It should be emphasized that postmortem and genetic studies have generally failed to show a sustained hyperactive dopamine system in schizophrenia, further supporting the idea that D2 antagonist treatment is not working through reducing postsynaptic dopamine function.

Why do D2 receptor antagonists have antipsychotic efficacy if there is no underlying dopamine hyperfunction in schizophrenia? One plausible mechanism may be as follows: while both D1 and D2 receptors are abundant in all dopamine-innervated regions, their ultrastructural localization is quite distinct. In particular, although D1 receptors are primarily, if not exclusively, localized postsynaptically, D2 receptors are localized extensively on presynaptic sites both on dopamine terminals and on non-dopamine terminals, including excitatory glutamatergic axons (Wang and Pickel 2002). The D2 receptors on dopamine terminals act as autoreceptors and tightly regulate the release of vesicular dopamine (Wolf et al. 1987). The D2 heteroreceptors on glutamate terminals are thought to mediate an inhibitory influence on glutamate release (Calabresi et al. 1992; Cepeda et al. 2001). Thus, blockade of dopamine D2 receptors increases the release of dopamine and glutamate, suggesting two possible mechanisms for the therapeutic efficacy of antipsychotic drugs: an increase in glutamate neurotransmission and activation of dopamine neurotransmission at D1 receptors. This is consistent with the ideas that there exists a D1 receptor deficiency in schizophrenia (Goldman-Rakic et al. 2004) and that NMDA receptors, as discussed below, may be hypofunctional in schizophrenia.

Glutamate Neurotransmission and Schizophrenia

Exposure to a single low dose of an NMDA receptor antagonist such as phencyclidine (PCP) or ketamine produces schizophrenia-like symptoms in healthy individuals and profoundly exacerbates preexisting symptoms in patients with schizophrenia (Javitt and Zukin 1991; Krystal et al. 1994; Lahti et al. 1995). The symptoms produced by these agents resemble positive and cognitive symptoms of schizophrenia, as well as disruptions in smooth-pursuit eye movements and prepulse inhibition of startle. These effects of NMDA receptor antagonists strongly suggest that glutamate neurotransmission at the NMDA receptor is compromised in schizophrenia (Moghaddam 2003).

In addition to the pharmacological evidence, other lines of work have implicated a role for glutamate neurotransmission in the etiology and pathophysiology of schizophrenia. For example, the majority of the genes that have recently been associated with an increased risk for schizophrenia can influence the function of modulatory sites on the NMDA receptor or intracellular-receptor interacting proteins that link glutamate receptors to signal transduction pathways (Harrison and Owen 2003; Moghaddam 2003). Postmortem studies show changes in glutamate receptor binding, transcription, and subunit protein expression in the prefrontal cortex, thalamus, and the hippocampus of subjects with schizophrenia (Clinton and Meador-Woodruff 2004). Examples include decreases in NR1 subunits of the NMDA receptor in the hippocampus and frontal cortical areas, high expression of excitatory amino acid transporters (EAATs) in the thalamus, and changes in the NMDA receptor-affiliated intracellular proteins such as PSD95 and SAP102 in the prefrontal cortex and thalamus. Another example includes amino acids N-acethylaspartate (NAA) and N-acethylaspartylglutamate (NAAG). Levels of NAA and the activity of the enzyme that cleaves NAA to NAAG and glutamate are altered in the CSF and postmortem tissue from individuals with schizophrenia (Tsai et al. 1995). NAAG is an endogenous ligand for the mGlu3 subtype of glutamate receptor, the gene for which has been implicated in increased propensity to develop schizophrenia. Furthermore, reduced NAA levels are thought to reflect decreased glutamate availability.

Recent imaging studies using a novel SPECT tracer for the NMDA receptor [123I]CNS-1261 (Pilowsky et al. 2005) have reported reduced NMDA receptor binding in the hippocampus of medication-free patients. While this study remains to be replicated in a larger group of patients, it represents the first direct demonstration of NMDA receptor deficiency in schizophrenia. Glutamate neurons regulate the function of other neurons that have been strongly implicated in the pathophysiology of schizophrenia. These include GABA interneuons whose morphology has been altered in schizophrenia (see below) and dopamine neurons, which are the target of antipsychotic drugs.

GABA Neurotransmission and Schizophrenia

Cortical GABAergic neurons are a diverse group of cells, consisting of several subsets that can be distinguished on the basis of morphological, electrophysiological, and biochemical characteristics (for review, please see Benes and Berretta 2001). One set of cortical GABAergic cells that appear to be particularly important in the pathophysiology of schizophrenia includes basket and chandelier neurons. Both of these cell populations have fast-spiking firing patterns, express the calcium-binding protein parvalbumin, and can be differentiated on the basis of their axonal projections. Basket cells are typically multipolar, having several primary dendrite branches, and project a large spread of axons that synapse primarily on pyramidal neuron cell bodies. These axo-somatic projections allow for a strong inhibitory effect on pyramidal cell-firing patterns. Chandelier neurons project axo-axonal terminals (termed cartridges) that synapse exclusively on the initial segment of pyramidal neuron axons. Moreover, these cartridges, which can be identified based on the expression of the GABA reuptake transporter GAT1, are positioned to veto the propagation of action potentials, and therefore also play an important inhibitory role in modulating pyramidal neuron output (Benes and Lange 2001).

There is now a growing line of evidence suggesting altered GABAergic neurotransmission in schizophrenia. Postmortem studies have reported reductions in the density of non-pyramidal cells in the PFC and anterior cingulate cortex (ACC) in patients with schizophrenia (Benes et al. 1991; Benes and Berretta 2001), as well as reductions in the number of parvalbumin-expressing cells in the PFC (Beasley and Reynolds 1997). Furthermore, patients with schizophrenia have significant increases in GABAA expression on pyramidal neurons in the PFC (Benes et al. 1996) and ACC (Benes et al. 1992), as well as a reduction in the number of cartridges expressing GAT1 (Woo et al. 1998; Pierri et al. 1999).

The most consistently altered marker of GABA function in schizophrenia is reduced expression of GAD67, which has been observed in at least two subtypes of GABA neurons in PFC subregions, including the DLPFC (Akbarian et al. 1995; Lewis et al. 2005). GAD67 accounts for the majority of GABA synthesis in the PFC. The reduced GAD67 function in subtypes of GABA neurons in schizophrenia, together with disruptions in GABAA and GAT1 expression (Benes et al. 1996; Woo et al. 1998; Pierri et al. 1999), strongly supports the idea that GABA availability is reduced in cortical synapses. It should, however, be mentioned that GABA synthesis, which is regulated via a process called the GABA shunt (Fig. 1), is quite complex in that reduced activity of GAD may also be reflective of a compensatory effect in response to sustained increases in GABA release. Increased levels of GABA have been shown to downregulate GAD activity in cultures and in specific regions of intact brain including the PFC (Rimvall et al. 1993; Sheikh and Martin 1998). Although postmortem studies in schizophrenia are not generally supportive of activated GABA function, the possible role of this mechanism should not be discounted.
Fig. 1

The GABA shunt is a closed-loop process with the dual purpose of producing and conserving the supply of GABA. The first step in the GABA shunt is the transamination of a-ketoglutarate (a-KG) by GABA transaminase (GABA-T) into glutamate. Glutamic acid decarboxylase (GAD) catalyzes the decarboxylation of glutamate to form GABA. GABA is metabolized by the enzyme GABA-T. To conserve the supply of GABA, this transamination occurs when a-KG molecule is present to accept the amino group removed from GABA, forming glutamate. Therefore, a molecule of GABA can be metabolized only if a molecule of precursor is formed

Disinhibition Hypothesis

Given the dominance of the dopamine hypothesis of schizophrenia, earlier attempts to consolidate theories that involved NMDA receptor or GABA deficiency involved a mechanistic cause and effect connection with dopamine hyperactivity. For example, earlier studies examining dopamine turnover or measuring the uptake of labeled dopamine showed that NMDA receptor antagonists increase the release of striatal dopamine (Bowyer et al. 1984; Hiramatsu et al. 1989). This finding contributed to initial versions of an integrated dopamine–glutamate theory, suggesting that NMDA receptor hypofunction may represent a model that mimicked the presumed dopamine hyperfunction state in schizophrenia (Javitt and Zukin 1991; Carlsson et al. 1993). This interpretation, however, could not account for the fact that NMDA receptor antagonists induce a far wider range of schizophrenia-like symptoms than the dopaminergic models and that many of their behavioral effects are independent of dopamine neurotransmission (Krystal et al. 1999). Thus, the theory was modified to include separate roles for cortical versus subcortical glutamate–dopamine interactions, in order to explain the induction of negative and cognitive symptoms in addition to positive symptoms (Weinberger 1987; Davis et al. 1991; Heinz et al. 2003). However, subsequent work using microdialysis or imaging methodologies showed that behaviorally relevant doses of NMDA antagonists do not increase striatal dopamine release in rodents, primate, or humans (Verma and Moghaddam 1996; Adams et al. 2002; Aalto et al. 2002), and dopamine antagonists such as haloperidol do not attenuate PCP-induced psychosis in humans (Aniline and Pitts 1982). Furthermore, behavioral studies have demonstrated that the aberrant behavioral effects of the NMDA receptor antagonists do not require dopamine (Carlsson and Carlsson 1990; Adams and Moghaddam 1998; Chartoff et al. 2005) and are not attenuated by dopamine antagonists (Bakshi et al. 1994; Corbett et al. 1995). These data, and the abundance of postmortem and genetic findings supporting a role for the glutamate system in the pathophysiology of schizophrenia, have led to the proposal that the primary abnormalities in schizophrenia may involve the synaptic signaling machinery in cortical regions and that a dopaminergic abnormality may be a consequence of cortical dysregulation of dopamine neurons. Interestingly, contrary to years of assertion that the PFC stimulates dopamine neuronal activity, stimulation of PFC neurons at physiological frequencies actually decreases dopamine release in the ventral striatum (Jackson et al. 2001). This suggests that the PFC exerts an inhibitory influence over subcortical dopamine presumably through the indirect activation of GABA neurons. Thus, reduced glutamatergic function in the PFC may remove this inhibitory influence and lead to an abnormally overactive subcortical dopamine system in schizophrenia. Recent electrophysiological studies recording from PFC cortical neurons in behaving rodents, in fact, show that a state of NMDA deficiency can lead to reduced burst activity of cortical neurons (Jackson et al. 2004).

Given the lack of direct evidence for a dopaminergic abnormality in schizophrenia, an alternative hypothesis has been that antipsychotic drugs, which are D2 receptor antagonists, work by modifying the function of cortical (glutamatergic) neurons. A substantial body of evidence demonstrates that dopamine modulates cortical and subcortical glutamatergic transmission (for review, see Seamans and Yang 2004). Notably, electrophysiological studies have revealed a delicate modulatory effect for dopamine on the electrical conductance of cortical excitatory neurons that is neither excitatory nor inhibitory but rather a gating effect that depends on the activity state of target neurons (Lavin and Grace 2001; Durstewitz 2006). Furthermore, D2 receptors may regulate the temporal organization of electrical activity in the PFC. D2 receptors also inhibit the release of glutamate (Koga and Momiyama 2000), suggesting that the blockade of D2 receptors by antipsychotic drugs can overcome a putative state of glutamate deficiency. In support of this mechanism, electrophysiological studies have shown that antipsychotic agents, particularly clozapine, exert positive modulatory effects on the NMDA receptor function in PFC and may attenuate the blockade of these receptors by NMDA receptor antagonists (Gemperle et al. 2003).

A related hypothesis has been that dopamine, GABA, and glutamate interactions may occur through modulating intricate postsynaptic intracellular mechanisms that mediate cross-talks between these transmitter systems in the prefrontal cortex. An example of this is depicted in Fig. 2. Regions other than the PFC that have been implicated in the pathophysiology of schizophrenia include regions such as the thalamus and hippocampus that provide substantial glutamate projections to PFC subregions. Reduced or dysregulated glutamatergic afferent activity from the thalamus or hippocampus could produce an NMDA hypofunction state in the PFC. A consequence of this may be reduced activity of GABA neurons, in particular parvalbumin-containing interneurons that are strongly driven by these inputs under normal conditions. This condition supports the postmortem findings of reduced GAD activity in the PFC. Inhibition of these neurons then results in dysregulation of PFC afferents leading to increased “noise” level (Jackson et al. 2004) and reduced ability to properly encode task-relevant events. One mechanism to ameliorate this is D2 inhibition (Homayoun and Moghaddam 2008) because activation of D2 (and not D1) receptors has been shown to reduce GABA-mediated inhibition of pyramidal neurons (Seamans and Yang 2004). The ideal pharmacological approach, however, would be to correct the dysregulated glutamate drive or its subsequent effects on inhibitory interneurons.
Fig. 2

A simplified circuit representing the basic interplay between glutamate, GABA, and dopamine neurotransmission in the cortex. Under normal conditions, glutamatergic afferents from cortical regions such as the thalamus and hippocampus drive the activity of GABAergic interneurons in the PFC, which serve to maintain inhibitory control of pyramidal neuron activity. Under conditions of NMDA hypofunction, GABAergic activity is reduced and tonic inhibitory control of pyramidal neuron activity is lost. Antagonism of dopamineric D2 receptors on glutamatergic terminals may increase glutamate release, restoring normal GABAergic inhibitory tone on pyramidal neuron activity

Thankfully, in the last few years these novel hypotheses are being tested by concrete data from animal and human laboratory studies. A new effort to test novel compounds that have are driven by logical design has begun (Patil et al. 2007; Lewis et al. 2008). After five decades of persevering on the first generation of antipsychotic drugs and the so-called “new generation” that have proved to not to have better efficacy than their antique counterparts (Geddes et al. 2000; Lieberman 2007), there is optimism that a truly new generation of antipsychotics that are more effective in treating schizophrenia is on the horizon.

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of NeuroscienceUniversity of PittsburghPittsburghUSA

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