Aberrant Hippocampal Activity Underlies the Dopamine Dysregulation in an Animal Model of Schizophrenia

Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 11/2007; 27(42):11424-30. DOI: 10.1523/JNEUROSCI.2847-07.2007
Source: PubMed
ABSTRACT
Evidence supports a dysregulation of subcortical dopamine (DA) system function as a common etiology of psychosis; however, the factors responsible for this aberrant DA system responsivity have not been delineated. Here, we demonstrate in an animal model of schizophrenia that a pathologically enhanced drive from the ventral hippocampus (vHipp) can result in aberrant dopamine neuron signaling. Adult rats in which development was disrupted by prenatal methylazoxymethanol acetate (MAM) administration display a significantly greater number of spontaneously firing ventral tegmental DA neurons. This appears to be a consequence of excessive hippocampal activity because, in MAM-treated rats, vHipp inactivation completely reversed the elevated DA neuron population activity and also normalized the augmented amphetamine-induced locomotor behavior. These data provide a direct link between hippocampal dysfunction and the hyper-responsivity of the DA system that is believed to underlie the augmented response to amphetamine in animal models and psychosis in schizophrenia patients.

Full-text

Available from: Anthony Grace, Oct 06, 2015
Neurobiology of Disease
Aberrant Hippocampal Activity Underlies the Dopamine
Dysregulation in an Animal Model of Schizophrenia
Daniel J. Lodge and Anthony A. Grace
Departments of Neuroscience, Psychiatry, and Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
Evidence supports a dysregulation of subcortical dopamine (DA) system function as a common etiology of psychosis; however, the factors
responsible for this aberrant DA system responsivity have not been delineated. Here, we demonstrate in an animal model of schizophre-
nia that a pathologically enhanced drive from the ventral hippocampus (vHipp) can result in aberrant dopamine neuron signaling. Adult
rats in which development was disrupted byprenatalmethylazoxymethanol acetate (MAM) administration display a significantly greater
number of spontaneously firing ventral tegmental DA neurons. This appears to be a consequence of excessive hippocampal activity
because, in MAM-treated rats, vHipp inactivation completely reversed the elevated DA neuron population activity and also normalized
the augmented amphetamine-induced locomotor behavior. These data provide a direct link between hippocampal dysfunction and the
hyper-responsivity of the DA system that is believedtounderlietheaugmentedresponsetoamphetamineinanimalmodelsandpsychosis
in schizophrenia patients.
Key words: hippocampus; schizophrenia; MAM; dopamine; psychosis; animal model
Introduction
The role of dopamine (DA) in schizophrenia is well established
based on the ability of DA agonists to exacerbate psychosis, the
efficacy of DA antagonists in treating schizophrenia, and imaging
studies of increased amphetamine-induced DA release in schizo-
phrenia (Laruelle and Abi-Dargham, 1999; Abi-Dargham, 2004).
Nonetheless, there is no evidence for a primary pathology within
the DA system itself in schizophrenia; rather, the DA system ap-
pears to be abnormally regulated (Grace, 1991, 2000; Abi-
Dargham, 2004). However, the mode of this dysregulation is un-
known. One model of DA function posits that the mesolimbic
DA system is regulated via two independent mechanisms: (1)
transient or “phasic” DA release driven by DA neuron burst firing
and (2) extrasynaptic or “tonic” levels DA dependent on basal DA
neuron activity and regulated via presynaptic inputs (Grace,
1991; Floresco et al., 2003). DA neuron burst firing induces a
large transient increase in perisynaptic DA (Chergui et al., 1994)
and is considered to be the functionally relevant signal that en-
codes reward prediction or incentive salience (Berridge and Rob-
inson, 1998; Schultz, 1998), whereas tonic DA transmission oc-
curs on a much slower scale and is proposed to set the
background level of DA system activation (Grace, 1991).
DA neuron activity is potently modulated by the ventral hip-
pocampus (vHipp) (Legault and Wise, 1999; Floresco et al., 2003;
Lodge and Grace, 2006a). Thus, vHipp activation increases DA
neuron population activity (i.e., number of DA neurons firing
spontaneously) without affecting average firing rate or burst fir-
ing and, moreover, this is dependent on a polysynaptic [vHipp–
nucleus accumbens (NAc)–ventral pallidum (VP)] projection
(Floresco et al., 2003; Lodge and Grace, 2006a). An increase in
population activity makes the DA system more responsive to
phasic activation by glutamatergic afferents (Lodge and Grace,
2006a). Given evidence correlating hippocampal dysfunction
with psychosis in schizophrenia (Harrison, 2004), we propose
that aberrant hippocampal activity may underlie the DA dysregu-
lation in this disorder.
Previous attempts to produce an animal model of schizophre-
nia have relied on developmental disruption. One model using
administration of the DNA methylating agent, methyla-
zoxymethanol acetate (MAM) to pregnant dams on gestational
day 17 (GD17) has substantial face validity in that the adult off-
spring demonstrate anatomical changes (thinning of limbic cor-
tices with increased neuronal packing density) (Moore et al.,
2006), behavioral deficits [decreased prepulse inhibition of star-
tle, disruption in learning new response contingencies, increased
responses to PCP (phencyclidine) and amphetamine (Flagstad et
al., 2004; Moore et al., 2006), an increased sensitivity to stress
(Goto and Grace, 2006), executive behavioral impairment
(Gourevitch et al., 2004), perseverative errors and deficits in la-
tent inhibition (Flagstad et al., 2004), and social impairment (Ta-
lamini et al., 1998; Talamini et al., 2000)], and disruption of
rhythmic activity in frontal cortex (Goto and Grace, 2006) that
parallels what has been observed in schizophrenia patients. Thus,
the MAM GD17 model recapitulates a pathodevelopmental pro-
cess leading to schizophrenia-like neuroanatomical and behav-
ioral phenotypes. Using this model, we now demonstrate the
Received June 22, 2007; revised Sept. 6, 2007; accepted Sept. 6, 2007.
This work was supported by United States Public Health Service Grants DA15408 and MH57440 (A.A.G.) and a
Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression, The Mental
Health Research Association (D.J.L.). We thank Niki MacMurdo and Christy Smolak for their valuable assistance and
Brian Lowry for the production, development, and support with the custom-designed electrophysiology software
(Neuroscope).
Correspondence should be addressed to Daniel J. Lodge, Department of Neuroscience, University of Pittsburgh,
A210 Langley Hall, Pittsburgh, PA 15260. E-mail: Lodge@bns.pitt.edu.
DOI:10.1523/JNEUROSCI.2847-07.2007
Copyright © 2007 Society for Neuroscience 0270-6474/07/2711424-07$15.00/0
11424 The Journal of Neuroscience, October 17, 2007 27(42):11424 –11430
Page 1
presence of a hippocampal dysfunction that leads to DA system
hyper-responsivity and provide new insights into understanding
the role of these systems in the pathophysiology of schizophrenia.
Materials and Methods
All experiments were performed in accordance with the guidelines out-
lined in the United States Public Health Service Guide for the Care and
Use of Laboratory Animals and were approved by the Institutional Animal
Care and Use Committee of the University of Pittsburgh.
Animals. MAM treatments were performed as described previously
(Moore et al., 2006). In brief, timed pregnant female Sprague Dawley rats
were obtained at GD15 and housed individually in plastic breeding tubs.
MAM (diluted in saline, 20 mg/kg, i.p.) was administered on GD17.
Control rats received injections of saline (1 ml/kg, i.p.). Within a week of
birth, offspring were culled to 10 by removal of female rats. Male pups
were weaned on day 21 and housed in groups of two to three with litter-
mates until 4 –5 months of age, at which time they were used for phys-
iological or behavioral studies. All experiments were performed on mul-
tiple litters of MAM- and saline-treated rats.
Acute studies. Adult male rats were anesthetized with chloral hydrate
(400 mg/kg, i.p.) and placed in a stereotaxic apparatus. Anesthesia was
maintained by supplemental administration of chloral hydrate as re-
quired to maintain suppression of limb compression withdrawal reflex
and a core body temperature of 37°C was sustained by a thermostatically
controlled heating pad. For acute administration of drugs into discrete
brain areas, rats were implanted with 23 gauge cannulas 2.0 mm dorsal to
the vHipp [anteroposterior (AP), 6.0; mediolateral (ML), 5.3; dor-
soventral (DV), 4.5 mm from bregma] and the pedunculopontine teg-
mental nucleus (PPTg; AP, 8.0; ML, 1.6; DV, 5.0 mm from
bregma) that were fixed in place with dental cement and two anchor
screws.
Pharmacological manipulations. Chemical stimulation was specifically
used to enable neuronal excitation without the confounds associated
with current spread, activation of fibers of passage, or potential lesions
during extended stimulation that may occur with electrical activation. All
drugs were dissolved in Dulbecco’s PBS (dPBS) and infused in a volume
of 0.5
l through a 30 gauge injection cannula protruding 2.0 mm past
the end of the implanted guide cannula. The injection cannula was left in
situ for 1–2 min to ensure diffusion of drug into the surrounding tissue.
NMDA (0.75
g/0.5
l) (Floresco et al., 2003; Lodge and Grace, 2006a),
tetrodotoxin (TTX; 1
M in 0.5
l) (Floresco et al., 2001), or vehicle
(dPBS) were all injected at doses reported previously to induce specific
behavioral and/or neurochemical effects.
The control group for DA neuron population studies consisted of rats
that received either no injection or vehicle (dPBS) infusions into the
vHipp and PPTg. Consistent with previous data (Lodge and Grace,
2006a) these groups all showed similar DA neuron population activity
parameters and their data were combined. Rats received only one injec-
tion per region and DA cell recordings were typically recorded from 10
min to 2 h after infusions.
VTA DA neuron extracellular recordings. Extracellular microelectrodes
(impedance, 6 –14 M) were lowered into the ventral tegmental area
(VTA; AP, 5.3; ML, 0.8 mm from bregma and 6.5 to 9.0 mm
ventral of brain surface) using a hydraulic microdrive and the activity of
the population of DA neurons was determined by counting the number
of spontaneously active DA neurons encountered while making 5–9 ver-
tical passes, separated by 200
m, in a predetermined pattern to sample
equivalent regions of the VTA. Spontaneously active DA neurons were
identified with open filter settings (low pass, 50 Hz; high pass, 16 kHz)
using previously established electrophysiological criteria (Grace and
Bunney, 1983) and, once isolated, their activity was recorded for 2–3
min. Three parameters of activity were measured: (1) population activity
(defined as the number of spontaneously active DA neurons recorded per
electrode track), (2) basal firing rate, and (3) the proportion of action
potentials occurring in bursts (defined as the occurrence of two spikes
with an interspike interval of 80 ms, and the termination of the burst
defined as the occurrence of an interspike interval of 160 ms) (Grace
and Bunney, 1983).
vHipp extracellular recordings. Extracellular microelectrodes (imped-
ance 6–12 M) were lowered into the ventral hippocampus (AP, 5.0;
ML, 4.5 mm from bregma and 5.0 to 8.5 mm ventral of brain
surface) using a hydraulic microdrive and spontaneously active neurons
throughout the vHipp were recorded while making 8 –12 vertical passes
(moving caudal and lateral), separated by 200
m, in a predetermined
pattern to sample equivalent regions of the vHipp. Once isolated, vHipp
neuronal activity was recorded for 3 min.
Amphetamine-induced locomotion. All survival surgical procedures
were performed under general anesthesia in a semisterile environment.
Briefly, male rats were anesthetized with ketamine/xylazine (80/12 mg/
kg, i.p., respectively) and placed in a stereotaxic apparatus using blunt
atraumatic ear bars. Bilateral cannulas (23 gauge) were implanted 2 mm
dorsal to the ventral hippocampus (AP, 6.0; ML, 5.3; DV, 4.5 mm
from bregma) and fixed in place with dental cement and four anchor
screws. Once the cement was completely solid, the wound was sutured,
the rat removed from the stereotaxic frame and monitored closely until
conscious. Rats received antibiotic treatment (gentamicin 3 mg/kg, s.c.)
and postoperative analgesia (Children’s Tylenol syrup in softened rat
chow; 5% v/w) ad libitum for 24 h. Rats were housed with a reverse
light/dark cycle (lights on from 7:00 P.M. to 7:00 A.M.) for at least 2
weeks before behavioral experiments. Rats were administered TTX (1
M) or vehicle (dPBS) bilaterally (0.5
l/side) and placed in an open field
arena (Coulbourn Instruments, Allentown, PA) where spontaneous lo-
comotor activity in the x–y plane was determined for 30 min by beam
breaks and recorded with TruScan software (Coulbourn Instruments).
Rats were then injected with
D-amphetamine sulfate (0.5 mg/kg, i.p.) and
locomotor activity recorded for an additional 60 min. It should be noted
that a subpopulation of rats were also tested for prepulse inhibition of
startle for the purpose of another study.
Histology. At the cessation of the electrophysiology experiments, the
recording site was marked via electrophoretic ejection of Pontamine sky
blue from the tip of the recording electrode (25
A constant current,
20 –30 min). For acute studies, rats were killed by an overdose of anes-
thetic (chloral hydrate, additional 400 mg/kg, i.p.), whereas for chronic
studies, rats were killed by a lethal dose of anesthetic (sodium pentobar-
bital, 120 mg/kg, i.p.). All rats were decapitated and their brains removed,
fixed for at least 48 h (8% w/v paraformaldehyde in PBS), and cryopro-
tected (25% w/v sucrose in PBS) until saturated. Brains were sectioned
(60
m coronal sections), mounted onto gelatin-chrom alum-coated
slides, and stained with cresyl violet for histochemical verification of
electrode and/or cannula sites. All histology was performed with refer-
ence to a stereotaxic atlas (Paxinos and Watson, 1986). Figure 1 provides
a representation of the localization of bilateral injection sites within the
ventral hippocampus.
Analysis. Electrophysiological analysis of DA and vHipp neuron activ-
ity was performed using custom-designed computer software (Neuro-
scope), whereas locomotor behavior was recorded using TruScan soft-
ware (Coulbourn Instruments). All data are represented as the mean
SEM unless otherwise stated. All statistics were calculated using the Sig-
maStat software program (Systat Software, San Jose, CA).
Materials. MAM was purchased from Midwest Research Institute
(Kansas City, MO). Ketamine HCl and xylazine were of United States
Pharmacopeia (USP) grade and purchased from Phoenix Pharmaceuti-
cal (St. Joseph, MO) whereas pentobarbital sodium (USP) was obtained
from Ovation Pharmaceuticals (Deerfield, IL). Chloral hydrate, NMDA,
tetrodotoxin, gentamicin solution, dPBS, and
D-amphetamine sulfate
were all purchased from Sigma (St. Louis, MO). All other chemicals and
reagents were of either analytical or laboratory grade and purchased from
various suppliers.
Results
Rats that received GD17 saline injections (n 5 rats, 45 neurons)
exhibited an average of 1.15 0.05 spontaneously active DA
neurons per electrode track that fired at an average rate of 3.94
0.27 Hz with 26.4 3.6% of action potentials fired in bursts,
consistent with previous findings in untreated rats (Floresco et
al., 2003; Lodge and Grace, 2006a,b). Adult rats administered
Lodge and Grace The Hippocampus, Dopamine, and Schizophrenia J. Neurosci., October 17, 2007 27(42):11424 –11430 11425
Page 2
MAM at GD17 (n 5 rats, 63 neurons) exhibited significantly
greater (approximately twofold) DA neuron population activity
(2.15 0.14 cell/track; p 0.05), without significant differences
in average burst firing (25.7 3.5%) or firing rate (4.40 0.25
Hz) relative to control. In control animals (n 5 rats, 62 neu-
rons), the simultaneous NMDA-induced activation of the vHipp
and PPTg resulted in a significant increase in DA neuron popu-
lation activity (2.07 0.12 cells/track; p 0.05) attributable to
vHipp activation (Fig. 2A), and a significant increase in average
burst firing (46.7 3.8%; p 0.05) attributable to PPTg activa-
tion (Fig. 2C) as reported previously (Lodge and Grace, 2006a).
In contrast, in MAM-treated rats (n 5 rats, 52 neurons), vHipp
activation failed to further increase DA neuron population activ-
ity (Fig. 2A) (1.86 0.04 cells/track), likely attributable to a
ceiling effect because it has been estimated that 50% of DA cells
are quiescent at rest (Grace et al., 2007). Interestingly, PPTg
afferent-induced burst firing remained intact (39.3 3.7%; p
0.05) (Fig. 2C).
Given evidence of hippocampal dysregulation in models of
schizophrenia, we examined whether the activity of the vHipp
was altered in MAM rats. Rats that received GD17 saline injec-
tions (n 4 rats, 59 neurons) exhibited an average firing rate of
0.54 0.11 Hz with 42 3% of action potentials fired in bursts,
an average within burst inter-spike interval (ISI) of 21.2 1.9 ms
and an average of 2.4 0.1 spikes per burst. In adult rats treated
prenatally with MAM (n 4 rats, 59 neurons), vHipp neurons
exhibited significantly higher (more than twofold) average firing
rates relative to control (1.34 0.25 Hz; p 0.05), without
significant differences in any burst firing parameter (average
Figure 1. A, Representative section demonstrating the localization of bilateral cannulas
placementsintheventralhippocampus.Theinjectionsitesaredenotedbyarrows.B,Schematic
illustrating the target injection sites within the ventral hippocampus (shaded area). Plate
adapted from Paxinos and Watson (1986).
Figure 2. A, C, Afferent modulation of DA neuron activity states in MAM- and SAL-treated
rats. In control rats (white bars), the simultaneous NMDA-induced activation of the vHipp and
PPTg (patterned bars) resulted in a significant increase in DA neuron population activity (A)
attributable to vHipp activation (Lodge and Grace, 2006a); and a significant increase in average
burst firing (C) attributable to PPTg activation (Lodge and Grace, 2006a). In contrast, in MAM-
treatedrats(darkbars),vHippactivationfailed to further increaseDAneuron population activity
(A), whereas PPTg afferent-induced burst firing (C) remained intact. B, The effect of NMDA-
induced afferent activation on average firing rate. An asterisk represents a statistically signifi-
cantdifference from control( p 0.05,one-wayANOVA, Student–Newman–Keuls post hocor,
if data failed tests for normality and/or equal variance, a Kruskal–Wallis one-way ANOVA on
Ranks, Dunn’s post hoc; n 5 rats/group). SAL, Saline-treated.
11426 J. Neurosci., October 17, 2007 27(42):11424 –11430 Lodge and Grace The Hippocampus, Dopamine, and Schizophrenia
Page 3
burst firing, 38 3%; average within burst ISI, 24.7 2.7 ms;
average spikes per burst: 2.7 0.2).
Given the role of the hippocampus in the regulation of DA
neuron population activity, we examined whether the observed
hippocampal overactivity may be responsible for the aberrant DA
neuron population activity. Intra-vHipp administration of the
sodium channel blocked TTX to MAM-treated rats (n 5 rats,
33 neurons) normalized the population activity to a level not
significantly different from control (0.99 0.12 cells/track) (Fig.
3A). Importantly, blockade of hippocampal transmission with
TTX did not significantly alter any parameter of DA neuron ac-
tivity in control rats ( n 5 rats, 41 neurons; population activity,
1.17 0.09 cells/track; firing rate, 3.83 0.26 Hz; burst firing,
26.9 3.9%) (Fig. 3A–C), nor did it affect firing rate (4.20 0.32
Hz) or burst firing (27.5 4.8%) in MAM-treated rats (Fig.
3B,C). It should be noted that no significant change in cells/track
within animals across time was observed, suggesting that the ef-
fect of TTX was not associated with diffusion into adjacent struc-
tures. Furthermore, it should be noted that this is a well estab-
lished technique used to examine the involvement of the vHipp
in numerous behavioral (Ambrogi Lorenzini et al., 1997; Zhang
et al., 2002; Degroot and Treit, 2004), neurochemical (Legault
and Wise, 1999; Peterschmitt et al., 2005), and electrophysiolog-
ical (Floresco et al., 2001) studies.
Given the previous literature demonstrating an increased be-
havioral responsivity to amphetamine in animal models of
schizophrenia, including MAM rats (Flagstad et al., 2004; Moore
et al., 2006), we suggest that this may be attributed to the en-
hanced baseline DA neuron population activity secondary to
vHipp hyperactivity. Consistent with previous observations
(Flagstad et al., 2004; Moore et al., 2006), MAM-treated rats dis-
played a significantly enhanced locomotor response (15% in-
crease above that produced in controls; p 0.05) to low dose (0.5
mg/kg, i.p.)
D-amphetamine administration (Fig. 4A). Further-
more, whereas bilateral hippocampal inactivation had no signif-
icant effect on amphetamine-induced locomotor activity in con-
trol animals (Fig. 4B), it significantly reduced the increased
psychostimulant-induced locomotion observed in MAM rats
(Fig. 4C). Taken as a whole, these data suggest that, in MAM rats,
a pathologically increased DA neuron population activity and
increased responsivity to amphetamine are attributable to basal
hippocampal hyperactivity.
Discussion
The data presented here demonstrate that MAM-treated rats dis-
play a pathologically enhanced DA neuron drive in the form of an
increase in DA neuron population activity. Moreover, this seems
to be associated with an increase in the spontaneous firing rate of
vHipp neurons unrelated to changes in patterned activity at the
single cell level. Furthermore, we suggest that the aberrant DA
neuron activity is attributed to the increased vHipp activity be-
cause intra-vHipp TTX administration normalizes both the
augmented DA neuron activity and the behavioral hyper-
responsivity to amphetamine. It is important to note that TTX
administration did not eliminate the response to amphetamine,
but instead restored it to the level found in controls.
An association between hippocampal activity and ascending
DA function has been suggested previously (Legault and Wise,
1999; Floresco et al., 2001, 2003; Lodge and Grace, 2006a). Thus,
the vHipp can modulate DA neuron population activity via a
multisynaptic (vHipp-NAc-VP-VTA) pathway (Floresco et al.,
2001, 2003). Furthermore, we have demonstrated previously that
the hippocampal modulation of DA neuron population activity is
not simply associated with the tonic release of DA in forebrain
regions, but also represents a recruitable pool of DA neurons that
can be further modulated by excitatory inputs to induce a graded
Figure 3. A–C, Inactivation of the vHipp by TTX (1
M; patterned bars) normalizes the
aberrant increase in DA neuron population activity in MAM rats (A), although has no observable
effectin control rats(whitebars;A–C) or onanyother DA neuronactivitystatein MAM rats(dark
bars;B, C). An asteriskrepresentsasignificant difference between vehicleandvHippinactivated
rats ( p 0.05, one-way ANOVA, Student–Newman–Keuls post hoc or, if data failed tests for
normality and/or equal variance, a Kruskal–Wallis one-way ANOVA on Ranks, Dunn’s post hoc;
n 5 rats/group). SAL, Saline-treated.
Lodge and Grace The Hippocampus, Dopamine, and Schizophrenia J. Neurosci., October 17, 2007 27(42):11424 –11430 11427
Page 4
phasic response (Lodge and Grace, 2006a). Therefore, increases
in vHipp activity will lead to an augmentation of DA system
responsivity. We now demonstrate that a pathologically en-
hanced hippocampal activity can result in aberrant DA neuron
signaling in a verified model of schizophrenia. Specifically, we
demonstrate that MAM-treated rats display a significantly higher
number of spontaneously active DA neurons compared with
control rats. Moreover, although PPTg afferent-induced burst
firing remained intact in MAM rats, additional activation of the
vHipp failed to induce additional increases in DA neuron popu-
lation activity in this model. We demonstrated previously the
importance of the hippocampal input in regulating not only the
tonic DA signal, but also the number of DA neurons capable of
conveying the phasic DA signal (Lodge and Grace, 2006a). As
such, the failure of hippocampal activation to increase DA neu-
ron population activity reflects a loss of a process critical for
regulating DA neuron output in MAM rats.
Given evidence of hippocampal dysregulation in schizophre-
nia, we examined whether activity within the ventral hippocam-
pus was altered in MAM-treated rats. Thus, the activity of vHipp
neurons is enhanced in MAM rats, expressed as a significantly
greater baseline firing rate with no significant change in patterned
activity at the single cell level. Because the hippocampus potently
modulates DA neuron population activity, this hippocampal hy-
peractivity may be responsible for the aberrant DA neuron pop-
ulation activity in MAM-treated rats. Indeed, TTX inactivation of
the vHipp normalized the pathologically enhanced DA neuron
population activity to a level consistent with that routinely ob-
served in control animals. This manipulation had no significant
effect on any other parameter of DA neuron activity in MAM rats
nor did it have any observable effects on DA neuron activity in
control animals. This lack of effect is consistent with the way the
hippocampus modulates DA neuron population activity, (i.e., via
a polysynaptic disinhibition of VTA activity) (Floresco et al.,
2001, 2003). More specifically, given that the ventral pallidum has
a high degree of spontaneous activity (10 Hz) (Johnson and
Napier, 1997), whereas cells of the NAc are largely quiescent
(Mulder et al., 1997) in the anesthetized rat, it is not surprising
that inhibition of hippocampal activity has little or no effect on
baseline DA cell activity.
There is a significant literature demonstrating an increased
responsivity to psychostimulants in both human schizophrenia
patients (Laruelle et al., 1996; Breier et al., 1997) and animal
models of schizophrenia, including MAM rats (Flagstad et al.,
2004; Moore et al., 2006). Moreover, vHipp activation has been
shown to increase the behavioral response to amphetamine in
normal rats (White et al., 2006). Therefore, we propose that the
source of amphetamine hyper-responsivity may be attributed to
vHipp-induced enhancement of baseline DA neuron population
activity. Whereas bilateral hippocampal inactivation had no sig-
nificant effect on amphetamine-induced locomotor activity in
control animals (consistent with the lack of effect observed on
DA cell activity), it significantly reduced the augmented
psychostimulant-induced locomotion observed in MAM rats.
Together, these data suggest that, in MAM rats, a pathologically
increased DA neuron population activity and increased respon-
sivity to amphetamine are attributable to basal hippocampal hy-
peractivity, although we have not tested whether the hyperactiv-
ity is present in the prepubertal animal, in which amphetamine
fails to cause hyperactivation in the MAM model. Moreover,
given the results of the present study, we propose that the hip-
pocampal dysfunction present in schizophrenia patients is the
basis for the hyper-responsive dopamine system proposed to un-
derlie psychosis in this disorder.
We suggested previously that disruption of hippocampal pro-
jections to the NAc may be a pathophysiological factor in schizo-
phrenia (Grace and Moore, 1998; O’Donnell and Grace, 1998;
Goto and Grace, 2005). The model advanced here is consistent
with hippocampal dysfunction observed in schizophrenia pa-
tients (Saykin et al., 1991; Harrison, 1999; Shenton et al., 2001)
and functional imaging studies show abnormally high activity
both during resting states (Nordahl et al., 1996; Heckers et al.,
1998; Lahti et al., 2006) and during task performance (Medoff et
al., 2001; Meyer-Lindenberg et al., 2001; Weiss et al., 2006). In
addition, an increase in hippocampal volume has been reported
in patients at the time of first psychotic break (Pantelis et al.,
2003), suggestive of hyperactivation within this structure. Fur-
thermore, hippocampal hyperactivity is proposed to underlie the
abnormal thought processes, hallucinations, and delusions in
this disorder (Krieckhaus et al., 1992; Venables, 1992). Finally, it
Figure 4. Bilateral vHipp inactivation by TTX (1
M) normalizes the aberrant locomotor
responseto
D-amphetamine(0.5 mg/kg i.p.) observedinMAM rats. A, MAM-treatedratsdisplay
an increased response to
D-amphetamine administration compared with saline-treated rats. B,
C, Inactivation of the vHipp by TTX significantly attenuates the locomotor response to
D-amphetaminein MAM rats (C) although hasnosignificant effect on psychostimulant-induced
locomotion in saline-treated (SAL) rats (B).
Significant difference from control ( p 0.05,
two-way ANOVA, Tukey’s post hoc; n 9 –17 rats/group).
11428 J. Neurosci., October 17, 2007 27(42):11424 –11430 Lodge and Grace The Hippocampus, Dopamine, and Schizophrenia
Page 5
is well known that temporal lobe epilepsy, a type of hyperactivity
of the hippocampus, has been associated with schizophrenia
symptoms in humans (Ounsted and Lindsay, 1981). Together,
these data are consistent with the model derived from the present
study, in which a hyperactive vHipp drives a DA hyperfunction.
However, whether this hyperactivity has its origin as a result of
pathology within the ventral hippocampus, or is driven abnor-
mally by another region, is not known at this time.
At face value, the hippocampal hyperactivity model of schizo-
phrenia may appear to be inconsistent with the neonatal ventral
hippocampal lesion (NVHL) model (Lipska et al., 1993). How-
ever, we suggest that both models may actually be producing a
similar pathology, but via different means. Thus, Swerdlow et al.
(2001) have demonstrated that the enhanced behavioral respon-
sivity to amphetamine in the NVHL model is attenuated with
extensive lesions encompassing the entire dorsal and ventral re-
gions of the hippocampus. On this basis, it has been suggested
that the behavioral abnormalities in the NVHL model reflect, at
least in part, aberrant function within spared elements of the
hippocampal complex (Swerdlow et al., 2001). Therefore, al-
though this increase in hippocampal activity has not been dem-
onstrated in the NVHL model, it is possible that in both models
the enhanced response to amphetamine derives from a hyperac-
tivity within hippocampal tissue.
The present study demonstrates that the pathological increase
in tonic DA transmission and aberrant responsivity to psy-
chomotor stimulants observed in MAM rats is likely attributable
to hyperactivity within the ventral hippocampus. Moreover, we
propose that the hippocampal dysfunction consistently observed
in schizophrenia patients is the basis for the dopamine dysregu-
lation in this disorder. We are of course aware that the adminis-
tration of a toxin to a developing rat is not an accurate recapitu-
lation of the etiology of schizophrenia in humans, nor is the
presence of simple deficits in sensory gating and executive func-
tion a necessary parallel to the complex cognitive and affective
deficits distinctive of this disorder. Nonetheless, we posit that at
the core of this disorder is a disruption of systems interactions
that can be modeled in animals, but when placed in the context of
complex human brain and behavioral patterns, yields the com-
plex pattern of psychopathology recognized as schizophrenia.
Such an understanding of the functional interactions among
these systems and how disruption within these circuits affects
information processing is central to gaining a better understand-
ing of disease pathophysiology and developing better pharmaco-
therapeutic agents.
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    • "For instance, SCZ has multifactorial origin which pervades the whole connectivity during neurodevelopment and results in poorly understood brain pathology. Human and animal research suggest that cortical and hippocampal inhibitory interneuron deficit contributes to the dopaminergic system dysfunction, thus the positive symptoms of SCZ [165]. In rodents, embryonic and induced human and nonhuman NPC grafts survive, proliferate, migrate, and differentiate spontaneously into pyramidal or GABAergic neurons166167168 . "
    [Show abstract] [Hide abstract] ABSTRACT: Neuronal differentiation of induced pluripotent stem cells and direct reprogramming represent powerful methods for modeling the development of neurons in vitro . Moreover, this approach is also a means for comparing various cellular phenotypes between cell lines originating from healthy and diseased individuals or isogenic cell lines engineered to differ at only one or a few genomic loci. Despite methodological constraints and initial skepticism regarding this approach, the field is expanding at a fast pace. The improvements include the development of new differentiation protocols resulting in selected neuronal populations (e.g., dopaminergic, GABAergic, hippocampal, and cortical), the widespread use of genome editing methods, and single-cell techniques. A major challenge awaiting in vitro disease modeling is the integration of clinical data in the models, by selection of well characterized clinical populations. Ideally, these models will also demonstrate how different diagnostic categories share overlapping molecular disease mechanisms, but also have unique characteristics. In this review we evaluate studies with regard to the described developments, to demonstrate how differentiation of induced pluripotent stem cells and direct reprogramming can contribute to psychiatry.
    Full-text · Article · Feb 2016 · Stem cell International
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    • "Administration of MAM, a DNA chelating agent, to pregnant dams at 15 GD or earlier disrupts normal fetal brain development and induces gross neurodevelopmental abnormalities both in the macro-and microstructure, particularly in cortical regions, and microcephaly (Singh, 1980;Jongen-Relo et al., 2004). When MAM is administered at a later stage during pregnancy (GD 17), less severe abnormalities with hyperdopaminergia were reported (Lodge and Grace, 2007;Du and Grace, 2013). On the other hand, maternal immune activation models recapitulate the effects of a maternal viral infection, activate microglia and cytokines production. "
    [Show abstract] [Hide abstract] ABSTRACT: Background. In utero exposure to maternal viral infections is associated with a higher incidence of psychiatric disorders with a supposed neurodevelopmental origin, including schizophrenia. Hence, immune response factors exert a negative impact on brain maturation that predisposes the offspring to the emergence of pathological phenotypes later in life. Although ventral tegmental area (VTA) dopamine neurons and their target regions play essential roles in the pathophysiology of psychoses, it remains to be fully elucidated how dopamine activity and functionality are disrupted in maternal immune activation models of schizophrenia.Methods. Here, we used an immune-mediated neurodevelopmental disruption model based on prenatal administration of the polyriboinosinic-polyribocytidilic acid [poly(I:C)] in rats, which mimics a viral infection and recapitulates behavioral abnormalities relevant to psychiatric disorders in the offspring. Extracellular dopamine levels were measured by brain microdialysis in both the nucleus accumbens shell and the medial prefrontal cortex, whereas dopamine neurons in VTA were studied by in vivo electrophysiology.Results. Poly(I:C)-treated animals, at adulthood, displayed deficits in sensorimotor gating, memory and social interaction and increased baseline extracellular dopamine levels in the nucleus accumbens, but not in the prefrontal cortex. In poly(I:C) rats dopamine neurons showed reduced spontaneously firing rate and population activity.Conclusions. These results confirm that maternal immune activation severely impairs dopamine system and that the poly(I:C) model can be considered a proper animal model of a psychiatric condition that fulfills a multidimensional set of validity criteria predictive of a human pathology.
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    • "The use of TTX has been investigated for medical purposes other than pain mitigation in animal models. These investigations include several urinary bladder dysfunction studies in pigs [127], treatment of drug addiction in rats [128], corneal injury induced photophobia in rats [129] or schizophrenia in rats [130]. Some researchers are trying to make use of the analgesic activity of TTX to treat various types of pains such as in severe cancer [29,34,119]. "
    [Show abstract] [Hide abstract] ABSTRACT: Tetrodotoxin (TTX) is a potent neurotoxin responsible for many human intoxications and fatalities each year. The origin of TTX is unknown, but in the pufferfish, it seems to be produced by endosymbiotic bacteria that often seem to be passed down the food chain. The ingestion of contaminated pufferfish, considered the most delicious fish in Japan, is the usual route of toxicity. This neurotoxin, reported as a threat to human health in Asian countries, has spread to the Pacific and Mediterranean, due to the increase of temperature waters worldwide. TTX, for which there is no known antidote, inhibits sodium channel producing heart failure in many cases and consequently death. In Japan, a regulatory limit of 2 mg eq TTX/kg was established, although the restaurant preparation of "fugu" is strictly controlled by law and only chefs qualified are allowed to prepare the fish. Due to its paralysis effect, this neurotoxin could be used in the medical field as an analgesic to treat some cancer pains.
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