number of spontaneously firing ventral tegmental DA neurons. This appears to be a consequence of excessive hippocampal activity
The role of dopamine (DA) in schizophrenia is well established
based on the ability of DA agonists to exacerbate psychosis, the
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)
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-
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-
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
lation in this disorder.
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
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-
lamini et al., 1998; Talamini et al., 2000)], and disruption of
rhythmic activity in frontal cortex (Goto and Grace, 2006) that
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
Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression, The Mental
11424 • TheJournalofNeuroscience,October17,2007 • 27(42):11424–11430
presence of a hippocampal dysfunction that leads to DA system
hyper-responsivity and provide new insights into understanding
All experiments were performed in accordance with the guidelines out-
lined in the United States Public Health Service Guide for the Care and
Care and Use Committee of the University of Pittsburgh.
Animals. MAM treatments were performed as described previously
MAM (diluted in saline, 20 mg/kg, i.p.) was administered on GD17.
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
controlled heating pad. For acute administration of drugs into discrete
the vHipp [anteroposterior (AP), ?6.0; mediolateral (ML), ?5.3; dor-
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
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
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
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.
(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
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
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
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).
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-
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-
a representation of the localization of bilateral injection sites within the
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
exhibited an average of 1.15 ? 0.05 spontaneously active DA
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
LodgeandGrace•TheHippocampus,Dopamine,andSchizophreniaJ.Neurosci.,October17,2007 • 27(42):11424–11430 • 11425
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-
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).
ity (Fig. 2A) (1.86 ? 0.04 cells/track), likely attributable to a
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,
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
illustrating the target injection sites within the ventral hippocampus (shaded area). Plate
A, Representative section demonstrating the localization of bilateral cannulas
PPTg (patterned bars) resulted in a significant increase in DA neuron population activity (A)
(A), whereas PPTg afferent-induced burst firing (C) remained intact. B, The effect of NMDA-
if data failed tests for normality and/or equal variance, a Kruskal–Wallis one-way ANOVA on
11426 • J.Neurosci.,October17,2007 • 27(42):11424–11430 LodgeandGrace•TheHippocampus,Dopamine,andSchizophrenia
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
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
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,
Hz) or burst firing (27.5 ? 4.8%) in MAM-treated rats (Fig.
within animals across time was observed, suggesting that the ef-
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-
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
a pathologically increased DA neuron population activity and
increased responsivity to amphetamine are attributable to basal
increase in DA neuron population activity. Moreover, this seems
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.,
not simply associated with the tonic release of DA in forebrain
A–C, Inactivation of the vHipp by TTX (1 ?M; patterned bars) normalizes the
LodgeandGrace•TheHippocampus,Dopamine,andSchizophrenia J.Neurosci.,October17,2007 • 27(42):11424–11430 • 11427
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
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
modulates DA neuron population activity, this hippocampal hy-
peractivity may be responsible for the aberrant DA neuron pop-
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
nor did it have any observable effects on DA neuron activity in
control animals. This lack of effect is consistent with the way the
a polysynaptic disinhibition of VTA activity) (Floresco et al.,
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
derlie psychosis in this disorder.
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-
abnormal thought processes, hallucinations, and delusions in
this disorder (Krieckhaus et al., 1992; Venables, 1992). Finally, it
C, Inactivation of the vHipp by TTX significantly attenuates the locomotor response to
locomotion in saline-treated (SAL) rats (B).†Significant difference from control ( p ? 0.05,
Bilateral vHipp inactivation by TTX (1 ?M) normalizes the aberrant locomotor
11428 • J.Neurosci.,October17,2007 • 27(42):11424–11430LodgeandGrace•TheHippocampus,Dopamine,andSchizophrenia
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,
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.
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.
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
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
complex human brain and behavioral patterns, yields the com-
plex pattern of psychopathology recognized as schizophrenia.
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