Int. J.

Devl Neuroscience 29 (2011) 215–223

Contents lists available at ScienceDirect

International Journal of Developmental Neuroscience

journal homepage: www.elsevier.com/locate/ijdevneu

Prefrontal cortical network connections: key site of vulnerability in stress and

schizophrenia
Amy F.T. Arnsten ∗
Department of Neurobiology, Yale Medical School, 333 Cedar St., New Haven, CT 06510, United States

a r t i c l e i n f o a b s t r a c t

Article history: The symptoms of schizophrenia involve profound dysfunction of the prefrontal cortex (PFC). PFC net-
Received 3 September 2010 works create our “mental sketch pad”, and PFC dysfunction contributes to symptoms such as cognitive
Received in revised form 2 February 2011 deficits, thought disorder, delusions and hallucinations. Neuropathological studies of schizophrenia have
Accepted 3 February 2011
shown marked loss of dendritic spines in deep layer III, the sublayer where PFC microcircuits reside. The
microcircuits consist of recurrent excitatory pyramidal cell networks that interconnect on spines, and
Keywords:
excite each other via NMDA receptor signaling. The pyramidal cell persistent firing is sculpted by lateral
Prefrontal cortex
inhibition from GABAergic basket and chandelier cells, thus creating tuned, persistent firing needed for
Catecholamines
Physiology
accurate representational knowledge (i.e., working memory). The strength of pyramidal cell network
cAMP connections is markedly and flexibly altered by intracellular signaling pathways in dendritic spines, a
DISC1 process called dynamic network connectivity (DNC). DNC proteins such as HCN channels are concen-
RGS4 trated on dendritic spines in deep layer III. Under optimal conditions, network inputs to pyramidal cells
Working memory are strengthened by noradrenergic alpha-2A inhibition of cAMP–HCN channel signaling, and sculpted by
dopamine D1-cAMP–HCN channel weakening of inappropriate inputs. However, with stress exposure,
high levels of cAMP–HCN channel signaling produces a collapse in network firing. With chronic stress
exposure, spines reduce in size and are lost, and this process involves increased PKC signaling. Impor-
tantly, molecules that normally strengthen PFC networks connections and/or reverse the stress response,
are often genetically altered in schizophrenia. As exposure to stress is a key factor in the precipitation
of schizophrenic symptoms, these dysregulated signaling pathways in deep layer III may interact with
already vulnerable circuitry to cause spine loss and the descent into illness.
© 2011 ISDN. Published by Elsevier Ltd. All rights reserved.

1. Overview termed dynamic network connectivity (DNC) (Arnsten et al., 2010).

Sustained activation of protein kinase C (PKC) and cAMP signaling
Schizophrenia is associated with altered prefrontal cortical pathways during chronic stress exposure contributes to dendritic
(PFC) circuits, arising from both developmental insults in utero (e.g., spine loss from layer III pyramidal cells, where DNC proteins are
as discussed in this issue), and continuing in the mature brain, concentrated (Arnsten, 2009). Deep layer III is also the site of PFC
e.g., with waves of gray matter loss in late adolescence and adult- pyramidal cell recurrent connections (Kritzer and Goldman-Rakic,
hood (Vidal et al., 2006; Sun et al., 2008) (Fig. 1A). Exposure to 1995; González-Burgos et al., 2000), and the sublayer where spine
stress is a key factor in the precipitation of symptoms in adoles- loss is particularly evident in schizophrenia (Glantz and Lewis,
cence and in subsequent exacerbation of symptoms (Breier et al., 2000). We posit that recurrent pyramidal cell network synapses are
1991; Nuechterlein et al., 1992; Miller et al., 2001; Dawson et al., particularly fragile, and that genetic insults – although expressed
2010), suggesting that the environment can interact with already globally – may have greater ramifications at this vulnerable site.
vulnerable circuitry to aggravate cortical deterioration. The current Understanding the processes that modulate these synaptic connec-
review focuses on mechanisms that may contribute to PFC network tions may provide the opportunity to protect PFC gray matter and
weakening in young adulthood, and the signaling pathways that prevent the descent into severe illness.
contribute to dendritic spine loss in response to stress.
We have discovered powerful intracellular signaling pathways 2. Prefrontal cortical dysfunction in schizophrenia
that rapidly alter the strength of PFC network connections, a process
The PFC guides behavior, thought and emotion using represen-
tational knowledge, a process often referred to as working memory
∗ Corresponding author. (Goldman-Rakic, 1995). This ability to represent, maintain and
E-mail address: [email protected] manipulate information that is no longer in the environment is

0736-5748/$36.00 © 2011 ISDN. Published by Elsevier Ltd. All rights reserved.

doi:10.1016/j.ijdevneu.2011.02.006
216 A.F.T. Arnsten / Int. J. Devl Neuroscience 29 (2011) 215–223

delay (Wilkins et al., 1987). Studies of human subjects also have

discovered remarkable roles for PFC circuits in metacognition and
insight, including feedback about what is real (Simons et al., 2008),
what we know (Jurado et al., 1998), and whether we are making
errors (Modirrousta and Fellows, 2008).
Patients with schizophrenia exhibit profound deficits in
PFC function that are fundamental components of this illness
(Weinberger et al., 1986; Barch, 2005; Keedy et al., 2006; Keefe
et al., 2006). For example, reduced activity in the right PFC during
a challenging working memory task highly correlates with symp-
toms of thought disorder (Perlstein et al., 2001). A patient with
severe limits in working memory abilities would be unable to hold
the initial goal of a sentence or thought long enough to sustain
its conclusion through the distraction of competing associations.
Foresight also has been positively associated with gray matter vol-
ume in the right PFC of patients with schizophrenia (Eack et al.,
2008). Patients sometimes describe a lack of foresight as an agoniz-
ing experience of being trapped in an eternal present, being unable
to envision even the near future, much like a small child who finds it
intolerable to wait (“Are we there yet?”). This impairment in cross-
temporal mediation (Fuster, 2000) may be present in both young
children with immature PFC function, and in patients, where PFC
has become dysfunctional.
The so-called “positive” symptoms of schizophrenia also involve
PFC dysfunction. Reduced activity of the right PFC is associated with
delusional thinking (Corlett et al., 2007). There is also evidence that
auditory hallucinations involve impaired communication between
the left PFC and Wernicke’s area (Ford et al., 2002). Normally,
the PFC emits a signal, termed efference copy (or corollary dis-
charge) to tag a response as internally generated. This suppresses
activity in Wernicke’s area during inner speech, and assigns the
voice as self-generated (Ford et al., 2002). Aberrations in corol-
lary discharge may interfere with this process and misassign
voices to an external source. Thus, there are likely many ways
in which dysfunctional PFC circuits contribute to symptoms of
schizophrenia.

3. Recurrent excitatory networks: the cellular basis of

Fig. 1. Prefrontal cortical circuitry and schizophrenia. (A) An overview of a possible working memory
progression of brain changes in schizophrenia. Genetic and/or environmental insults
alter the precise formation of cortical pyramidal cell microcircuits in utero. These
insults continue to weaken NMDA-mediated, pyramidal cell connections in the Extensive research has identified the PFC microcircuits that
maturing brain, particularly during adolescence when there are normal rearrange- underlie spatial working memory in monkeys (Fig. 1B). The abil-
ments of cortical circuitry. Layer III pyramidal cell recurrent microcircuits may be ity to represent a visuospatial position arises from recurrent
particularly vulnerable, as this layer is the focus of spine loss in schizophrenia. Loss
excitation between pyramidal cells in deep layer III of area 46
of NMDA microcircuit activity leads to a variety of compensatory changes, includ-
ing reduction in GABAergic actions, reduced DA inputs to PFC, and increased DA (Kritzer and Goldman-Rakic, 1995), the dorsolateral PFC surround-
inputs to caudate. Reductions in GABA may contribute to weaker oscillatory activity ing the caudal principal sulcus (Goldman-Rakic, 1995). This PFC
in brain. Reductions in both GABA and D1 receptor stimulation in PFC would erode region receives highly processed visuospatial information from the
information processing in PFC, increasing inappropriate network inputs. Increased parietal association cortex, and even small lesions to this area
DA inputs in caudate magnify cortical errors to contribute to thought disorder, hal-
lucinations and delusions. Adapted from Lewis and Gonzalez-Burgos (2006) with
produce permanent deficits in spatial working memory abilities
emphasis on vulnerability of pyramidal cell recurrent connections. (B) The layer (Funahashi et al., 1993). The recurrent excitatory circuits inter-
III PFC microcircuits that subserve spatial working memory in primate dorsolat- connect on dendritic spines (e.g., Fig. 2), which have recently
eral PFC. Based on the work of Goldman-Rakic and colleagues (Goldman-Rakic, been shown to depend on NMDA receptor stimulation (Arnsten
1995).
et al., 2010). Thus, pyramidal cells with similar spatial charac-
teristics excite each other to keep information “in mind” over a
thought to be the foundation of abstract thought, and the neural delay period when there is no information available in the envi-
basis of our “mental sketch pad”. As eloquently described by Fuster ronment.
(2008), persistent firing by PFC neurons is able to “wed the past Representation of a visuospatial position also requires spatial
to the future” (so-called cross-temporal mediation; Fuster, 2000), tuning, such that the neuron fires to the memory of one region of
allowing us to plan ahead for the end of a sentence or the start visuospace but not to others. This is accomplished in part through
of a career. The PFC is critical for flexible, high order decision- lateral inhibition by GABAergic interneurons (Rao et al., 1999; Rao
making (Lee et al., 2007) and top-down regulation of attention et al., 2000). In particular, parvalbumin-containing basket cells and
(Knight et al., 1995; Buschman and Miller, 2007), including the sup- interneurons provide spatial tuning, as shown in Fig. 1B. Thus, inhi-
pression of interference (Thompson-Schill et al., 2002), set-shifting bition of GABAa receptors leads to noisy neuronal response to all
(Robbins, 2007), and the ability to sustain attention over a long spatial directions (Rao et al., 1999, 2000).
 A.F.T. Arnsten / Int. J. Devl Neuroscience 29 (2011) 215–223 217

synaptic strength of recurrent PFC network connections (Arnsten

et al., 2010). Specifically, schizophrenia is often associated with
alterations in molecules that normally serve to strengthen connec-
tions, and to protect PFC networks from the detrimental effects of
stress.

5. Molecular regulation of PFC excitatory networks:

dynamic network connectivity

Recent research has revealed that the physiological strength

of PFC network connections dynamically changes in coordination
Fig. 2. Some of the DNC signaling pathways that regulate PFC network strength, with arousal state. Molecular signaling events in the spines of PFC
and their relationship to schizophrenia; mechanisms that strengthen connectivity pyramidal dendrites can open or close ion channels near synaptic
are shown in green; those that weaken connectivity are shown in red. Genetic alter-
connections to rapidly and reversibly alter the strength of network
ations in patients with schizophrenia frequently involve DNC proteins that normally
serve to strengthen pyramidal cell connections, and to inhibit stress signaling path-
inputs (Wang et al., 2007). Importantly, these DNC signaling pro-
ways (shown in purple). Thus, these genetic insults would weaken PFC network teins are concentrated in deep layer III (Arnsten et al., 2010), the site
connections and increase vulnerability to stress exposure. (For interpretation of the of PFC microcircuits (Kritzer and Goldman-Rakic, 1995), and of the
references to color in this figure legend, the reader is referred to the web version of greatest spine loss in schizophrenia (Glantz and Lewis, 2000). We
the article.)
propose that these molecular events, in combination with the chal-
Adapted from Arnsten et al. (2010).
lenge of sustaining neural activity in the absence of “bottom-up”
environmental stimulation, make layer III PFC recurrent connec-
4. Dendritic spine loss in layer III of patients with tions the “weakest link” in higher cognitive functioning (Arnsten
schizophrenia et al., 2010).
A schematic illustration of DNC mechanisms is presented in
Neuropathological studies of dorsolateral PFC from patients Fig. 2, whereby specific network connections onto spines can be
with schizophrenia have shown reduced neuropil (Selemon et al., weakened via calcium and/or cAMP–PKA increasing the open state
1998) and loss of dendritic spines (Glantz and Lewis, 2000), par- of potassium channels localized on spines near excitatory, NMDA
ticularly in deep layer III where PFC recurrent microcircuits reside. synapses. The ability to rapidly and reversibly weaken a network
Lewis and Gonzalez-Burgos (2006) have described a cascade of pri- connection may serve several purposes. Under optimal arousal con-
mary genetic insults to PFC pyramidal cell circuits, followed by ditions, a specific subset of network inputs can be weakened (e.g.,
compensatory events that may combine to produce the symptoms as with dopamine D1 receptor stimulation described below), to
of schizophrenia (a variation on this scheme is presented in Fig. 1A): dynamically alter the breadth of network inputs based on current
cognitive demands. Global weakening of network inputs may also
1) Neurodevelopmental errors caused by genetic and/or environ- serve key roles in (1) providing negative feedback to constrain over-
mental insults as the cortex develops in utero, leading to the excitability in recurrent excitatory circuits, (2) conserving energy
formation of abnormal PFC circuitry, followed by under conditions of fatigue, and (3) rapidly taking PFC “off-line”, in
2) progressive PFC spine loss in adolescence and continuing into response to danger, to switch control of behavior to more primitive
adulthood, leading to greatly reduced pyramidal cell network brain regions that mediate instinctive reactions. For example, high
excitation. The weakening of pyramidal cell network activity levels of catecholamine release during stress exposure drives the
would then lead to a number of compensatory changes: production of cAMP (Fig. 2), which disconnects PFC networks but
3) weakening of specific (parvalbumin-containing) GABA synapses strengthens the emotional and habitual responses of the amygdala
due to loss of excitatory drive from pyramidal cell networks. and basal ganglia (Arnsten, 2009). The loss of PFC cognitive func-
The expression of the synthetic enzyme for GABA, GAD67, is tion with even mild, uncontrollable stress has now been observed
dependent on NMDA stimulation from pyramidal cell networks in both animals and humans, and likely contributes to a broad range
(Kinney et al., 2006), and GAD67 is markedly reduced in the PFC of mental illnesses (reviewed in Arnsten, 2009).
of patients with schizophrenia (Volk et al., 2000). The reduction There are also DNC mechanisms that inhibit the stress
in GABA would in turn reduce neuronal network tuning, and response and strengthen network connections. PFC connections
thus make information noisier; are strengthened when cAMP signaling is inhibited, potassium
4) reduced cortical drive on DA neurons projecting to PFC. As channels close, and other, depolarizing channels (e.g., TRPC) are
described below, this would further erode spatial tuning, and opened. For example, noradrenergic stimulation of alpha-2A recep-
alter the timing of corollary discharge. A compensatory increase tors strengthens network firing during the delay by inhibiting
in D1 receptors in PFC may also magnify the stress response and cAMP–HCN channel signaling in spines, preferentially increasing
contribute to spine loss, also described below; and the neuron’s response to its preferred direction (Wang et al., 2007).
5) increased DA release in caudate, which would magnify cortical This specific pattern of response is thought to arise from selective
inputs and PFC network errors. localization of alpha2A receptors on spines receiving inputs from
pyramidal cells with shared tuning properties (schematically dia-
It is also possible that the primary genetic insult in some fami- grammed in Fig. 3). Similarly, DISC1 (disrupted in schizophrenia)
lies could afflict GABA interneurons (Gonzalez-Burgos et al., 2010), is found in spines in the primate PFC (Kirkpatrick et al., 2006), and
leading to compensatory reductions in NMDA signaling and the is known to regulate cAMP through interactions with the phos-
emergence of a similar phenotype. Indeed, a major challenge for phodiesterases, enzymes that catabolize cAMP (Millar et al., 2007;
current research is to determine how so many different genetic Murdoch et al., 2007). The ability to precisely control the amount
insults can all lead to similar neuropathology and symptoms. In this and location of cAMP actions within a PFC pyramidal cell may define
context, it is remarkable that a large number of already-identified the quality and extent of its network connections, and thus the
genetic insults in schizophrenia are DNC proteins that regulate the cellular basis of cognitive content.
218 A.F.T. Arnsten / Int. J. Devl Neuroscience 29 (2011) 215–223

For example, attentional set-shifting likely requires broad inputs,

and this ability is impaired by D1 receptor actions in PFC (Granon
et al., 2000). These data indicate that dopamine D1 sculpting actions
must be dynamically regulated according to momentary cogni-
tive demands to provide optimal modulation, e.g., slightly higher
dopamine release for tasks requiring narrow tuning (e.g., remem-
bering 90◦ , as shown in Fig. 3), and less dopamine release for
cognitive challenges needing wider network inputs (combining 90◦
and 45◦ , or combining spatial and feature information, as shown in
Fig. 3). These data may also explain why insightful, “out-of-the box”
solutions are more likely to arise when a subject has no pressure
to perform (Subramaniam et al., 2008; Arnsten et al., 2009). Alto-
gether, the dopamine D1 receptor findings highlight the need for
precise regulation of network connections, and thus the need for
precise regulation of D1-cAMP signaling.

Fig. 3. Recordings from PFC neurons indicate that network inputs from neurons
7. Chronic stress: sustained weakening of PFC network
with similar vs. dissimilar tuning characteristics are modulated differently. Nora-
drenergic stimulation of ␣2A-AR strengthens delay-related firing for a neuron’s connections leads to spine loss
preferred direction, suggesting that these receptors modulate network inputs from
neurons with shared stimulus properties (e.g., as shown in this example, strengthen- While acute stress induces a transient, physiological weakening
ing inputs from other 90◦ neurons). In contrast, dopamine D1 signaling can weaken of PFC network connections, exposure to chronic stress additionally
network connections from neurons with dissimilar characteristics, (e.g., weakening
inputs from a 45◦ neuron). We have proposed that D1 receptor stimulation may also
induces architectural changes in PFC pyramidal cells. Chronic stress
weaken network inputs from other cortical areas, (e.g., visual feature information causes dendritic retraction and loss of spines, and these structural
arriving from area 45), thus determining the breadth of network inputs. changes are associated with impaired PFC function (Radley et al.,
Based on Arnsten et al. (2009). 2008), including severe working memory loss (Hains et al., 2009).
Weakened PFC connectivity has even been seen in humans under-
going a mild, sustained stress (Liston et al., 2009). Spine loss can
6. Dopamine D1 receptor stimulation: the double-edged also be induced in PFC through chronic exposure to corticosterone,
sword and is associated with reduced NMDA receptors and BDNF levels
(Gourley et al., 2009), suggesting that some aspects of the stress
Dopamine D1 receptors are localized on dendritic spines near response may be mediated through this hormone. In normal sub-
excitatory network inputs in the primate dorsolateral PFC (Smiley jects, these architectural changes in animals and humans reverse
et al., 1994). For over 20 years, it has been appreciated that once the stressor is removed (Liston et al., 2009). However, environ-
D1 receptor stimulation produces an inverted U dose response, mental and genetic insults can reduce resilience to stress exposure.
whereby either too little or too much impairs working memory For example, in studies of rodent PFC, architectural changes have
performance (Arnsten and Goldman-Rakic, 1990; Arnsten et al., been observed in the adult offspring of mothers who were stressed
2009). Total blockade of D1 receptors appears to reduce all neuronal during pregnancy (Murmu et al., 2006).
firing, likely due to the loss of fundamental excitatory influences The signaling events that underlie stress-induced spine loss are
(reviewed in Arnsten et al., 2009). However, D1 receptors also beginning to be explored. Sustained elevation of protein kinase C
have powerful effects on PFC network inputs. Recent studies show (PKC) signaling may contribute, as increased PKC activity has been
that DA D1 receptor stimulation weakens network inputs via observed in PFC in response to stress exposure (Birnbaum et al.,
increased cAMP signaling (Vijayraghavan et al., 2007). Under opti- 2004). In vitro studies of hippocampal pyramidal cells have shown
mal conditions during a spatial working memory task, D1 receptor that sustained activation of PKC induces spine loss through phos-
stimulation weakens the neuron’s response to nonpreferred spatial phorylation of MARCKS, unanchoring MARCKS from the membrane,
directions, and thus reduces “noise” and sharpens spatial tuning which in turn leads to collapse of the spine’s actin cytoskeleton
(Vijayraghavan et al., 2007). In vitro recordings from PFC slices in (Calabrese and Halpain, 2005) (schematically illustrated in Fig. 4).
both rat (Gorelova et al., 2002) and monkey (Kroner et al., 2007) Similar results were observed in vivo in the rat PFC, where inhibition
indicate that sculpting actions may also arise from D1 activation of PKC signaling prevented spine loss and protected working mem-
of fast-spiking interneurons, and possible reductions in presynap- ory performance during chronic stress exposure (Hains et al., 2009).
tic glutamate release (Gao et al., 2001). All of these mechanisms Sustained elevations in PKC signaling also induce actin collapse in
may combine to restrict neuronal firing. Thus, inadequate D1 recep- growth cones (Torreano et al., 2005) and microspikes (Yokoyama
tor stimulation leads to noisy neuronal firing, with PFC neurons et al., 1998), the latter via pMARCKS as well.
firing during the delay to the memory of all spatial directions Preliminary evidence indicates that inhibition of cAMP signal-
(Vijayraghavan et al., 2007). However, under conditions of very high ing may also protect PFC structure and function from chronic stress
levels of D1 receptor stimulation – as occurs during stress expo- (Arnsten, unpublished). It is not known how sustained elevation
sure (Murphy et al., 1996) – all PFC networks are disconnected, of cAMP signaling leads to spine loss rather than enlargement
and all memory-related firing is suppressed (Vijayraghavan et al., in PFC. Like PKC, increased cAMP-PKA signaling can defibrillize
2007). Neuronal firing patterns are restored via inhibition of cAMP actin in microspikes (Fleming et al., 2004), perhaps through unan-
signaling (ibid). These powerful D1 actions may contribute to the choring actin via FAK (Serrels et al., 2010). The findings that
rapid loss of dorsolateral PFC functions with exposure to even mild, elevated PKC and cAMP signaling may cause defibrillation of actin
uncontrollable stressors. in both microspikes and PFC spines during stress exposure suggests
Although spatial working memory for a small region of visu- these very different cellular processes may share some essen-
ospace benefits from D1 sculpting actions, other PFC cognitive tial regulatory processes (although PKA reduces actin filaments
operations that rely on broad network inputs can actually be in microspikes by inhibiting RhoA signaling (Fleming et al., 2004),
harmed by dopamine D1 receptor actions (Arnsten et al., 2009). while activation of RhoA signaling causes spine loss in hippocampal
 A.F.T. Arnsten / Int. J. Devl Neuroscience 29 (2011) 215–223 219

Fig. 4. RGS4 inhibition of PKC signaling may protect PFC gray matter from the detrimental effects of chronic stress exposure. (A) RGS4 is abundant in PFC neurons, and is
localized near synapses in dendritic spines in monkey dorsolateral PFC (Paspalas et al., 2009). (B) A possible signaling mechanism whereby RGS4 inhibits Gq-PKC signaling
in spines. Sustained increases in PKC signaling are known to cause collapse of the actin cytoskeleton and spine loss via phosphorylation of MARCKS, which in turn unanchors
actin from the membrane (see text). (C) Exposure to chronic stress induces working memory deficits and spine loss from layer III PFC pyramidal cells in rats. Inhibition of
PKC signaling during stress exposure protects working memory and dendritic spines, and there is a significant correlation between these measures. Thus, loss of RGS4 in
schizophrenia may leave patients more vulnerable to spine loss. Black, control conditions; red, saline treatment during chronic stress exposure; blue, PKC inhibition under
control conditions, green, PKC inhibition during chronic stress exposure. (For interpretation of the references to color in this figure legend, the reader is referred to the web
version of the article.)
Adapted from Hains et al. (2009).

neurons (Sfakianos et al., 2007). Interestingly, microspikes forma- of these genes have been confirmed by GWAS, the working model
tion relies on CDC42 signaling, a molecule that is reduced in layers indicates how even rare genetic alterations may produce a similar
III–VI in the dorsolateral PFC of patients with schizophrenia (Hill phenotype if they also weaken key PFC networks.
et al., 2006; Ide and Lewis, 2010). It is possible that reductions in NMDA receptor signaling – PFC network firing during work-
CDC42 interact with DNC stress pathways in layer III to contribute ing memory depends on glutamate actions at NMDA receptors on
to preferential spine loss in layer III in patients. pyramidal cell spines (Arnsten et al., 2010 and Wang and Arn-
Spine loss may also occur through reductions in NMDA receptor sten, unpublished). The reduction in NMDA receptor signaling in
actions. Stress-like neurochemical conditions markedly suppress schizophrenia is widely discussed, and may arise from a number of
neuronal firing in the monkey PFC (Birnbaum et al., 2004; factors, including genetic insults to such NMDA regulatory proteins
Vijayraghavan et al., 2007). If these conditions are sustained in as NRG1 and dysbindin (reviewed in Krystal et al., 2003; Ross et al.,
chronic stress, large reductions in network firing would lead to 2006; Javitt, 2010; Kristiansen et al., 2010). Reduced NMDA recep-
reduced glutamate stimulation of NMDA receptors. Recent stud- tor signaling can lead to spine shrinkage and loss (Hayashi-Takagi
ies have shown that decreases in NMDA signaling lead to spine et al., 2010), suggesting that both functional and architectural dys-
shrinkage via DISC1 sequestration of Kalirin-7 in the synapse and function can arise from these insults (see above). NMDA receptors
inhibition of rac1 signaling (Hayashi-Takagi et al., 2010). It is likely have also been reported on GABAergic interneurons, although this
that multiple, interacting pathways lead to spine loss during stress, may only occur during adolescence (Wang and Gao, 2009). Thus,
and understanding these molecular events will be key to rescuing the impact of altered NMDA signaling on GABAergic interneuronal
gray matter loss in patients with schizophrenia. function may only contribute during a discrete but important time
period (Belforte et al., 2010).
8. Genetic insults to “molecular brakes” on stress pathways Nicotinic ␣7 receptors – nicotinic ␣7 receptors are depolarizing,
in schizophrenia cation channels that have been localized on dendritic spines in the
rat PFC, in addition to their traditional presynaptic location (Duffy
A variety of signaling events can strengthen PFC network con- et al., 2009). Behavioral studies have shown that stimulation of ␣7
nections and/or provide brakes on the stress response to restore receptors strengthens the working memory and attention functions
PFC network connectivity. A remarkable number of these molecules of the PFC, e.g., (Levin et al., 2006; Boess et al., 2007; Chan et al.,
have been associated with genetic insults in schizophrenia (shown 2007), including reversal of cognitive deficits induced by NMDA
in purple in Fig. 2), which would lead to weakened network con- receptor blockade (Buccafusco and Terry, 2009). Our recent data
nections and dysregulation of the stress response. Although not all show that stimulation of ␣7 receptors in PFC strengthens memory-
220 A.F.T. Arnsten / Int. J. Devl Neuroscience 29 (2011) 215–223

related firing, while blockade of this receptor markedly reduces 9. Dopamine actions in schizophrenia
PFC network firing in monkeys performing a working memory task
(Yang et al., 2010). Genetic alterations of the ␣7 receptor have been Dopamine is dysregulated in schizophrenia. A long and consis-
linked to attentional gating deficits in patients with schizophre- tent history has shown excessive DA stimulation of D2 receptors in
nia for many years (Leonard and Freedman, 2006; Martin and caudate (Wong et al., 1986; Seeman et al., 1989; Laruelle et al., 1996;
Freedman, 2007; Severance and Yolken, 2008). It is possible that the Kegeles et al., 2010), and more recent work suggests reduced DA in
high prevalence of smoking in patients with schizophrenia arises PFC post-mortem, at least at later ages (Akil et al., 1999). As there is
from their need to increase nicotine stimulation of ␣7 receptors likely increased DA innervation of layer III in the PFC during adoles-
to strengthen PFC network connections. Nicotinic a7 agonists are cence (Rosenberg and Lewis, 1995), there may be a hyperDA state
currently being developed as potential cognitive enhancers that during this key time period, which rapidly erodes with advanc-
may be especially useful in patients with schizophrenia (Hajós and ing age. As shown in Fig. 1A, the dysregulation of DA in PFC and
Rogers, 2010; Thomsen et al., 2010). caudate is likely secondary to insults in PFC circuits that normally
RGS4 and PI/PKC signaling – RGS4 inhibits Gq signaling, and control DA activity (Lewis and Gonzalez-Burgos, 2006). Dopamine
thus can reduce a number of cellular actions, including IP3 cal- dysregulation would likely have multiple consequences.
cium release (Fig. 2) and PKC signaling (Fig. 4). RGS4 protein and D1 receptor signaling in PFC: PET imaging studies have shown
mRNA are greatly reduced in the PFC of patients with schizophre- increased D1 receptor binding in PFC in schizophrenia that cor-
nia (Mirnics et al., 2001; Erdely et al., 2006; Volk et al., 2010), and relates with cognitive deficits (Abi-Dargham et al., 2002). The
several genetic studies have found links between RGS4 and mental upregulation in D1 receptors is thought to be a compensatory
illness (Chowdari et al., 2002; Morris et al., 2004; Fallin et al., 2005). response to reduced DA stimulation (Guo et al., 2003). Given that
Loss of RGS4 would disinhibit Gq signaling, potentially amplifying optimal DA D1 receptor stimulation in PFC requires rapid, dynamic
the effects of alpha-1, 5HT2 and mGluR1/Gq signaling in the spine changes based on cognitive demands, it is likely that D1 recep-
and reducing PFC network activity (Fig. 2B and D). Recent stud- tor stimulation is often suboptimal in patients with schizophrenia,
ies have also observed an increase in mGluR1a mRNA in the PFC with
of patients with schizophrenia (Volk et al., 2010), further driving
Gq signaling and reducing neuronal firing. As shown in Fig. 4, loss a) inadequate D1 receptor stimulation under basal conditions,
of RGS4 would also disinhibit PKC signaling, which could aggra- leading to noisy firing and inappropriate network connections,
vate spine loss (Hains et al., 2009). In support of this hypothesis, perhaps contributing to loose associations, and
polymorphisms in RGS4 are associated with PFC gray matter loss, b) excessive D1 receptor stimulation suppressing all firing under
reduced connectivity and reduced BOLD signals in patients with conditions such as mild stress when there is increased DA
schizophrenia (Prasad et al., 2005; Buckholtz et al., 2007). release onto upregulated D1 receptors (Vijayraghavan et al.,
DISC1 and cAMP signaling – a translocation in the gene encoding 2007; Fig. 1A).
for DISC1 has been associated with high rates of mental illness in
a large Scottish pedigree (Millar et al., 2000, 2005). Genetic insults These data suggest that patients with schizophrenia would have
to DISC1 likely contribute to altered cortical development (Ishizuka narrowed inverted U’s with a limited range of optimal modulation,
et al., 2006), and may also lead to weakened network connectivity. and thus be especially vulnerable to stress (Arnsten et al., 2009).
DISC1 is localized in dendritic spines in the primate PFC (Kirkpatrick One can speculate that this would be further aggravated in patients
et al., 2006), and interacts with the cAMP-catabolizing enzyme, with genetic insults in DISC1 and/or PDE4 signaling with dysreg-
PDE4 (Millar et al., 2007; Murdoch et al., 2007). DISC1 is thought to ulation of cAMP signaling (Arnsten et al., 2009). Exaggerated D1
activate PDE4s under conditions of high cAMP production to pro- receptor signaling also might contribute to spine loss during stress
vide negative feedback. Thus, loss of DISC1 function should lead to exposure.
increased cAMP in spines, as shown in Fig. 2. As described above, D2 receptor signaling in PFC: in contrast to D1 recep-
increased cAMP signaling in suppresses PFC neuronal firing, and tor modulation of delay-related firing, D2 receptors modulate
may also contribute to spine loss during chronic stress. Prelimi- response-related firing (Wang et al., 2004). Interestingly, some of
nary data from our lab show that knockdown of DISC1 in the rat the responses of PFC neurons occur during the motor response,
medial PFC lowers the threshold for stress-induced PFC dysfunc- and are thought to represent corollary discharge. D2 recep-
tion (Gamo et al., 2010). In this regard it is particularly interesting tor stimulation increases response-related firing, and speeds the
that a DISC1 polymorphism is associated with increased psychosis, response, while reduced D2 receptor stimulation slows and reduces
cognitive dysfunction, and PFC gray matter loss in patients with response-related firing (Wang et al., 2004). Alterations in either the
schizophrenia (Cannon et al., 2005; Szeszko et al., 2008). timing and/or the amplitude of corollary discharge may interfere
Interestingly, significant associations have been observed with the “mental tag” that denotes that a response is self-generated
between reduced PFC BOLD activity and single nucleotide poly- (Arnsten et al., 2009). In humans, D2 alterations in PFC may
morphisms in genes encoding for DISC1, NMDA, ␣7 nicotinic interfere with corollary discharge emanating from Broca’s area,
and ␣2A adrenergic receptors in an fMRI study of patients with contributing to auditory hallucinations (Ford et al., 2002).
schizophrenia performing an oddball task (Liu et al., 2009). Thus, D2 receptor signaling in caudate: as described above, exten-
this nonbiased study uncovered a set of DNC-associated proteins sive evidence documents increased DA D2 receptor stimulation in
needed for strong PFC function. the caudate of patients with schizophrenia. Dopamine D2 recep-
These data may explain why such a wide variety of genetic tor signaling normally serves to disinhibit the indirect pathways
insults can lead to a similar phenotype of weakened PFC net- through the basal ganglia, thus increasing motor, cognitive and
work firing. Although it is unlikely that treatments will be able to affective responses (Steiner and Gerfen, 1998). The caudate is
correct abnormalities in PFC circuit formation that have occurred the striatal structure mediating cognitive responses, and receives
during development, there is hope that we may be able to ame- extensive inputs from the association cortices (Alexander et al.,
liorate some of the genetic errors in DNC proteins that weaken 1986). Thus, excessive D2 receptor stimulation in caudate would
PFC circuits with targeted medications. The appropriate treatment magnify incoming cortical errors (Fig. 1A).
at key time periods, e.g., in adolescence, may slow the progres- Increased DA release during stress exposure could thus lead
sion of PFC network demise and the manifestation of schizophrenia to a constellation of detrimental actions: disconnection of PFC
symptoms. networks, inaccurate timing of corollary discharge from PFC, and
 A.F.T. Arnsten / Int. J. Devl Neuroscience 29 (2011) 215–223 221

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Disclosures Corlett, P.R., Murray, G.K., Honey, G.D., Aitken, M.R., Shanks, D.R., Robbins, T.W., Bull-
more, E.T., Dickinson, A., Fletcher, P.C., 2007. Disrupted prediction-error signal
in psychosis: evidence for an associative account of delusions. Brain 130 (Pt. 9),
AFTA and Yale University receive royalties from Shire Pharma- 2387–2400.
ceuticals for the sale of Intuniv (extended release guanfacine) for Dawson, M.E., Schell, A.M., Rissling, A., Ventura, J., Subotnik, K.L., Nuechterlein, K.H.,
the treatment of ADHD and related disorders. AFTA receives funds 2010. Psychophysiological prodromal signs of schizophrenic relapse: a pilot
study. Schizophr. Res. (Epub ahead of print).
from Shire for research related to ␣2A noradrenergic signaling Duffy, A.M., Zhou, P., Milner, T.A., Pickel, V.M., 2009. Spatial and intracellular rela-
mechanisms, and performs consulting and speaking engagements tionships between the alpha7 nicotinic acetylcholine receptor and the vesicular
with Shire. AFTA also has previously received research funds from acetylcholine transporter in the prefrontal cortex of rat and mouse. Neuro-
science 161, 1091–1103.
Marinus Pharmaceuticals for the development of the PKC inhibitor,
Eack, S.M., George, M.M., Prasad, K.M., Keshavan, M.S., 2008. Neuroanatomical sub-
chelerythrine, for the treatment of mental illness. strates of foresight in schizophrenia. Schizophr. Res. 103, 62–70.
Erdely, H.A., Tamminga, C.A., Roberts, R.C., Vogel, M.W., 2006. Regional alterations
in RGS4 protein in schizophrenia. Synapse 59, 472–479.
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The research in this article was supported by Public Health A.E., 2005. Bipolar I disorder and schizophrenia: a 440-single-nucleotide poly-
morphism screen of 64 candidate genes among Ashkenazi Jewish case-parent
Service grants PO1 AG030004, MERIT Award AG06036, and trios. Am. J. Hum. Genet. 77, 918–936.
1RL1AA017536 within U54RR024350, and a NARSAD Distinguished Fleming, Y.M., Frame, M.C., Houslay, M.D., 2004. PDE4-regulated cAMP degrada-
Investigator Award to AFTA. tion controls the assembly of integrin-dependent actin adhesion structures and
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