cocaine depresses IGABA

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Maternal Exposure to Interleukin-2 Induces
Long-Lasting Increases in Behavioral and
Neuronal Responses to Novelty and Psychostimulant
Challenge in Offspring Steven S.
Zalcman, Alba Rossi-George, Jessica Hu, Mark D.
Bobbin, Janet Worobiej, Nicholas M. Ponzio
UMD-NJ Medical School, Departments of Psychiatry
and Pathology, 183 South Orange Ave. Newark New
Jersey 07103

Effects of Maternal IL-2 Exposure on Fos-like
Immunoreactivity in GBR 12909-Treated Offspring
Introduction
Effects of Maternal IL-2 Exposure on
Novelty-Induced Behavior in Offspring
Maternal immune activation is thought to
increase vulnerability to psychiatric disorders
involving repetitive and stereotypic behavior
(notably schizophrenia and autism). Interleukin
(IL)-2 is a TH1-derived cytokine that potently
modulates dopamine activity and neuronal
excitability in mesolimbic and mesostriatal
structures (Lapchak, 1992 Alonso et al., 1993
Zalcman et al., 1994 Anisman et al., 1996
Pettito et al., 1997 Song et al., 1999 Ye et
al., 2001). IL-2 also acts as a potent
neuromodulator. For example, IL-2 influences the
survival of hippocampal, septal, striatal,
cerebellar, and cortical neurons, and promotes
neurite extension, and growth and survival of
septohippocampal neurons. We showed that
interleukin IL-2 potentiates novelty- and
psychostimulant-induced locomotion (Zalcman et
al., 1998 Zalcman, 2001). As well, mice
receiving repeated injections of IL-2 (once a day
for 5 days) display marked increases in
stereotypic motor behavior (Zalcman, 2002). In
light of these effects of IL-2, it might not be
surprising that it is implicated in
neurodevelopmental disorders that involve the
expression of repetitive and motor stereotypies
(notably, schizophrenia, autism). We thus
hypothesized that maternal exposure to IL-2
induces long-term behavior-activating effects in
offspring, and potentiates behavioral and
neuronal responses to psychostimulant challenge.
Materials and Methods SJL/J mice were housed
3-4 females per male in breeding cages. Pregnant
females received an in injection of PBS or murine
IL-2 (PeproTech Inc., Rocky Hill, NJ 0.4
mg/mouse) once a day for 5 days during the second
trimester. Offspring were weaned at PND 21,
housed in standard polypropylene cages,
maintained on a 12 hour light / 12 hour dark
cycle, and permitted ad lib access to food and
water. Adult offspring were tested for behavioral
responses to novelty stress (i.e, exposure to a
novel environment) and psychostimulant challenge
(i.e., an injection of 5 mg/kg GBR 12909
Tocris-Cookson). Test sessions were taped with a
VHS camera and scored at a later date by an
experienced rater. The frequency of stereotypic
behavior was determined every 30-min in 1-min
epochs after GBR challenge by an experienced
rater who was blind to the treatment groups.
Frequency was defined as the duration of time
during each observation period that the mouse was
engaged in motor stereotypies.A modification of a
scale developed by Creese and Iverson (1972) and
Capper-Loup et al. (2002) was used where
0undetectable, 1very weak, 2weak, 3weak to
moderate, 4 moderate, 5moderate to strong,
6strong, 7intense, 8very intense, and 9
extreme.
Fig. 1-2 Pregnant SJL/J mice received
injections of vehicle or murine IL-2 (0.4 mg, IP
once/day for 5-days) during the second trimester.
Adult offspring of IL-2-treated dams displayed
marked increases in rearing (Fig. 1) within
10-min of exposure to a novel environment. In
male offspring, the number of grooming episodes
was also significantly increased (Fig. 2).
Fig. 5 Pregnant SJL/J mice received
injections of vehicle or murine IL-2 (0.4 mg, IP
once/day for 5-days) during the second trimester.
Adult male offspring received a single
injection of GBR 12909 (5 mg/kg, IP). Offspring
of IL-2-treated dams showed significant increases
in Fos-like immunoreactivity in the septal area
2-hr after challenge with a single injection of
GBR 12909.
Fig. 1
Fig. 2
Fig. 5
Summary and Conclusions
Effects of Maternal IL-2 Exposure on Stereotypic
Behavior following Psychostimulant Challenge

• Adult male offspring of IL-2-treated dams
  displayed marked increases in novelty-induced
  rearing and grooming behavior compared with PBS
  controls.
• Adult male offspring of IL-2-treated dams
  displayed marked increases in levels of
  stereotypic behavior following a single injection
  of GBR 12909, a DA uptake inhibitor with
  stimulant-like properties.
• GBR-stimulated c-fos expression was increased in
  the septum as a function of maternal IL-2
  treatment.
• This is the first evidence that prenatal IL-2
  exposure (1) produces very long-lasting
  behavior-activating effects in offspring, (2)
  potentiates the expression of dopamine-dependent
  stereotypy, and (3) augments stimulant-induced
  neuronal activation in limbic structures. We
  suggest that increased maternal IL-2 levels
  during pregnancy could induce in offspring a
  long-lasting increased vulnerability to
  neurobehavioral abnormalities associated with
  dimensions of schizophrenia and autism. Since
  behavioral effects were most pronounced in male
  offspring, we suggest that this study has
  implications on the development of a model of
  autism.
• Supported by NIH/NIMH, National Alliance for
  Autism Research, NJ Governors Council on Autism.
  

Fig. 3-4 Pregnant SJL/J mice received injections
of vehicle or murine IL-2 (0.4 mg, IP once/day
for 5-days) during the second trimester. Adult
male offspring showed significant increases in
the frequency of stereotypic motor behavior after
challenge with a single injection of GBR 12909
(5 mg/kg, IP), a dopamine uptake inhibitor with
stimulant-like properties.
Fig. 4
Fig. 3