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-Amino Butyric Acid (GABA) and Glutamate in Control of Puberty in Female Rhesus Monkeys: Effect of an Antisense Oligodeoxynucleotide for GAD67 Messenger Ribonucleic Acid and MK801 on Luteinizing Hormone-Releasing Hormone Release1
Wisconsin Regional Primate Research Center (E.K., C.L.N., K.M., E.T.) and Department of Pediatrics (E.T.), University of Wisconsin-Madison, Madison, Wisconsin 53715-1299
Address all correspondence and requests for reprints to: Ei Terasawa, Ph.D., Wisconsin Regional Primate Research Center, 1223 Capitol Court, Madison, Wisconsin 53715-1299. E-mail: terasawa{at}primate.wisc.edu
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Abstract |
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-aminobutyric acid (GABA) is an
inhibitory neurotransmitter restricting the pubertal increase in LHRH
release in juvenile monkeys, and that interfering with GABA synthesis
with an antisense oligodeoxynucleotide (AS) for glutamic acid
decarboxylase (GAD67) mRNA results in an increase in LHRH release in
prepubertal monkeys. GAD67 is a catalytic enzyme that synthesizes GABA
from glutamate. To further clarify the role of GABA in puberty, we
examined whether the inhibition of LHRH release by GABA continues after
the onset of puberty and whether input from glutamatergic neurons plays
any role in the onset of puberty when GABA inhibition declines, using a
push-pull perfusion method. In Study I, the effects of the AS GAD67
mRNA on LHRH release in pubertal monkeys (34.3 ± 1.5 months of
age, n = 8) were examined, and the results were compared with
those in prepubertal monkeys (18.5 ± 0.4 months, n = 12).
Direct infusion of AS GAD67 (1 µM) into the stalk-median
eminence (S-ME) for 5 h stimulated LHRH release in both
prepubertal and pubertal monkeys. However, the increase in LHRH release
in pubertal monkeys was significantly (P < 0.01)
smaller than that in prepubertal monkeys. Infusion of a scrambled oligo
as a control was without effect in either group. In Study II, to
examine the possibility that an increase in glutamate tone after the
reduction of an inhibitory GABA tone contributes to the AS
GAD67-induced LHRH increase, the effects of the NMDA receptor blocker
MK801 (5 µM) on LHRH release were tested in monkeys
treated with AS GAD67. MK801 infusion into the S-ME during the
treatment of AS GAD67 (1 µM) suppressed the AS
GAD67-induced LHRH release in both age groups. MK801 alone did not
cause any significant effect in either group. The data are interpreted
to mean that GABA continues to suppress LHRH release after the onset of
puberty, although the degree of suppression is weakened considerably
after the onset of puberty, and that the increased LHRH release after
AS GAD67 treatment may be partly due to an increase in glutamate tone
mediated by NMDA receptors, as well as due to the decrease in GABA
release following the decrease in GAD synthesis. Taken together, the
present results suggest that GAD may play an important role in the
onset and progress of puberty in nonhuman primates. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-amino butyric acid (GABA) is responsible for the
low levels of LHRH release in prepubertal monkeys and the removal of
this inhibition triggers the onset of puberty (4, 7). This hypothesis
is based on the observations that 1) GABA release in the stalk-median
eminence (S-ME) in prepubertal monkeys was much higher than that in
pubertal monkeys (7); 2) the direct infusion of bicuculline, a
GABAA receptor antagonist, into the S-ME induced a dramatic
increase in LHRH release in prepubertal monkeys, whereas it increased
LHRH release only slightly in pubertal monkeys (7); and 3) GABA
infusion suppressed LHRH release in pubertal, but not in prepubertal
monkeys (7). Subsequently, we have shown that infusion of antisense
oligodeoxynucleotides for glutamic acid decarboxylase (GAD) mRNAs into
the S-ME of prepubertal monkeys stimulated LHRH release (8). GAD is the
catalytic enzyme for GABA synthesis from glutamate, and there are two
forms of GAD (GAD67 and GAD65) with different molecular weights (67 kDa
and 65 kDa, respectively) derived from two respective genes (9, 10).
The antisense oligodeoxynucleotides presumably interfered with GAD
synthesis, leading to a decrease in GABA synthesis and release, and
resulting in the increase in LHRH release (8). Input from glutamatergic neurons has also been postulated as an important factor for the pubertal increase in LH release and in LHRH release (3, 11, 12, 13). N-methyl-D-aspartate (NMDA), a stimulant for the glutamate receptor NMDA subtype, or glutamate, induces LHRH release in prepubertal and pubertal rat hypothalami in vitro (11, 14, 15), LH and LHRH release in vivo in prepubertal as well as in pubertal monkeys (16, 17, 18, 19, 20), and administration of NMDA induced precocious puberty in female rats and male monkeys (21, 22), whereas treatment with MK801, a specific antagonist of NMDA receptors, delayed the timing of puberty in female rats (23).
Because both GABA and glutamate are major neurotransmitters for inhibitory and excitatory signals in the hypothalamus, respectively, it is possible that an increase in glutamate tone is associated with the decrease in GABA tone at the onset of puberty. To understand the role of GABA and glutamate in puberty, therefore, we conducted two experiments. In Study I we examined whether GABA inhibition continues after the onset of puberty by testing the effects of an antisense oligodeoxynucleotide for GAD67 mRNA (AS GAD67) on LHRH release in both prepubertal and pubertal monkeys using a push-pull perfusion method in vivo. Because in the previous study (8) AS GAD67 induced substantially larger effects than AS GAD65, we used AS GAD67 in this study. In Study II, to examine the possibility that an increase in glutamate tone after the reduction of an inhibitory GABA tone contributes to the AS GAD67-induced LHRH increase, the effects of the NMDA receptor blocker MK801 on LHRH release were tested in monkeys treated with AS GAD67.
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Materials and Methods |
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Push-pull perfusion
The push-pull perfusion method was very similar to that
described elsewhere (24, 25). A cranial pedestal was implanted on the
skull under isoflurane anesthesia. The third ventricle and bone
structures were visualized with x-ray ventriculograms before pedestal
implantation. The monkeys were allowed to recover for at least 4 weeks
before the initiation of push-pull perfusion experiments. Monkeys were
adapted to a primate chair, the experimental environment, and the
investigators.
Three days before the push-pull perfusion, the animals were anesthetized with ketamine (10 mg/kg BW) and xylazine (1–2 mg), and were placed in a stereotaxic apparatus for cannula implantation. An outer cannula (20 gauge) with a stylet (27 gauge) was inserted into the S-ME using a microdrive unit (MO95-B, Narishige, Tokyo, Japan). x-ray ventriculograms at the time of pedestal implantation were used as reference points for the placement of the cannula tip. After cannula implantation, the monkey was placed in a primate chair. On the day of the perfusion experiment, the stylet was replaced with an inner cannula (29 gauge) and infusion was started. A modified Krebs-Ringer phosphate buffer solution (artificial CSF) was infused using a peristaltic pump (Minipulse 3, Gilson Electronic, Middleton, WI) into the S-ME through the push cannula at a rate of 23 µl/min, while perfusates were collected on ice through the pull cannula using an identically calibrated pump. Perfusate samples were collected at 10-min intervals, and each 150 µl of sample was aliquoted into a vial and stored at -70 C until assayed for LHRH.
Experimental design
Study I. Previously we showed that infusion of an antisense
oligodeoxynucleotide for GAD67 mRNA (AS GAD67) into the S-ME of
prepubertal monkeys resulted in a large increase in LHRH release. To
determine whether AS GAD67 also increases LHRH release in pubertal
monkeys (34.8 ± 1.9 months), AS GAD67 was infused into the S-ME
using a push cannula, whereas perfusate samples were collected through
a pull cannula. The results were then compared with those in
prepubertal monkeys (18.7 ± 0.6 months). Since in a previous
study (8) AS GAD67 induced substantially larger effects on LHRH release
than AS GAD65, we used AS GAD67 in this study. The methods for AS GAD67
infusion were similar to those described previously (8). Based on DNA
sequence of monkey GAD67 (8), AS GAD67 (5'-GAA GAT GGG GTC GAA GAC
GC-3') and an oligodeoxynucleotide that contains the same bases in
scrambled sequence (SC GAD67, 5'-TAG GAG CAG ACT GAG AGG CG-3') for
control were synthesized at the Biotechnology Center, University of
Wisconsin-Madison (Madison, WI). The oligodeoxynucleotides were
desalted and resuspended in artificial CSF under sterile conditions.
After 4 h of control perfusion, AS GAD67 or SC GAD67 (1
µM) was continuously infused into the S-ME for 5 h,
which was followed by an additional 5 h of control perfusion. LHRH
levels in the perfusate samples were measured by RIA.
Study II. There is a possibility that an increase in glutamate tone after the reduction of an inhibitory GABA tone contributes to the AS GAD67-induced LHRH increase. To test this possibility, the effects of the NMDA receptor blocker, MK801 (5 µM, Research Biochemicals International, Natick, MA), on LHRH release were examined in monkeys treated with AS GAD67. Five micromolars of MK801, a noncompetitive NMDA receptor antagonist, was infused simultaneously with AS GAD67 into the S-ME of prepubertal (18.9 ± 0.5 months) and pubertal (33.6 ± 2.4 months) monkeys. The infusion protocol was similar to that in Study I: after 4 h of control infusion, artificial CSF containing MK801 (5 µM) and AS GAD67 (1 µM) was infused for 5 h, followed by additional 5 h of control perfusion. As a control, MK801 in artificial CSF was similarly infused. LHRH levels in the perfusates were determined by RIA. We conducted studies I and II concurrently, so that the effects of MK801 plus AS GAD67 could be compared with those of AS GAD67 alone in each age group.
LHRH RIA
LHRH in perfusates (150 µl) was measured by RIA using
antiserum R1245, kindly provided by Dr. T. Nett (Colorado State
University, Fort Collins, CO), as described previously (24). Synthetic
LHRH (Richelieu Biotechnologies Inc., Montréal, Québec,
Canada) was used for the radiolabeled antigen and reference standard.
The antigen-antibody complex was precipitated with a sheep antirabbit
-globulin. Sensitivity of the assay was 0.1 pg/tube, and intra and
interassay coefficients of variation were 11.7% and 15.7%,
respectively.
Data analysis
The effects of AS GAD67 on mean LHRH levels and the effects of
MK801 on the AS GAD67-induced LHRH release were determined by 2-way
ANOVA for repeated measures, followed by post hoc analysis
with the Student-Newman-Keuls’ test. For statistical analysis the data
during the first hour of the experiment was not included because high
LHRH levels were sometimes observed during the initial period of
infusion. Mean LHRH levels in each hour period before the
oligodeoxynucleotide infusion were compared with those in each hour
period during and after the infusion of the oligodeoxynucleotides. In
Study I, hourly mean values of AS GAD67 were compared with
corresponding hourly mean values of SC GAD67 within the same age group.
Hourly mean values of AS GAD67 between the two age groups were also
compared. Further, the magnitude of the LHRH response to AS GAD67
between prepubertal and pubertal groups was compared by calculating the
difference between mean LHRH levels during the control period and those
during and after AS GAD67 infusion. In Study II, hourly mean values of
the AS GAD67 and MK801 treatment were compared with those of the MK801
treatment alone. In addition, hourly mean values of AS GAD67 treatment
with MK801 from Study II were compared with corresponding data of AS
GAD67 from Study I because the two studies were conducted concurrently.
For graphic expression, normalized data are used: in each animal, the
mean LHRH levels in the 3-h period before the oligodeoxynucleotide
infusion was designated as 100%, and the mean LHRH levels in each 1-h
period before and after the initiation of the oligodeoxynucleotide
infusion were calculated accordingly. Statistical significance was
attained at P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and 2). An increase in LHRH release started
2–3 h after the initiation of AS GAD67 infusion and lasted until after
the termination of AS GAD67 infusion in prepubertal (Fig. 1A) and in
pubertal monkeys (Fig. 1B). However, the AS GAD67-induced LHRH release
in pubertal monkeys was consistently smaller than in prepubertal
monkeys. SC GAD67 infusion did not cause any significant effects on
LHRH release in either prepubertal or pubertal animals (Fig. 1, C and
D).
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, A and B) and pubertal monkeys
(P < 0.01, Fig. 2, C and D). The post hoc
analysis further indicated that, in prepubertal monkeys, an increase
(P < 0.01 to 0.05) in mean LHRH release occurred
during the second hour after the initiation of AS GAD67 infusion, and
the increase lasted until 5 h after the termination of the
antisense infusion when compared with the preinfusion levels (Fig. 2A).
Similarly, in pubertal monkeys, an increase (P < 0.01
to 0.05) in mean LHRH release started during the third hour after the
initiation of AS GAD67 infusion, and the increase lasted for the entire
period of the experiment (Fig. 2B). Although the difference between the
hourly mean LHRH over time in pubertal monkeys (Fig. 2B) vs.
prepubertal monkeys (Fig. 2A) did not attain statistical significance
(P = 0.08), the LHRH increase (7.6 ± 1.2 pg/ml)
in response to AS GAD67, calculated by the difference in LHRH levels
during/after AS GAD67 infusion and before AS GAD67 treatment, in the
prepubertal group were significantly (P < 0.01) larger
than that (3.2 ± 0.6 pg/ml) in the pubertal group.
Effects of MK801 on the AS GAD67-induced LHRH release in
prepubertal and pubertal monkeys (Study II)
Simultaneous infusion of MK801 with AS GAD67 suppressed the AS
GAD67-induced LHRH increase in both prepubertal (Fig. 3A) and pubertal (Fig. 3B) monkeys.
Infusion of MK801 alone did not induce any significant changes in LHRH
release in prepubertal monkeys (Fig. 3C). However, in pubertal monkeys
MK801 infusion suppressed LHRH release in five of eight cases, as shown
in one example in Fig. 3D, whereas MK801 failed to change LHRH release
in the remaining three cases.
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) and pubertal (P <
0.01, Fig. 4B) monkeys. Infusion of MK801 alone did not induce any
significant changes in LHRH release in prepubertal monkeys (Fig. 4C) or
in pubertal monkeys (Fig. 4D). The overall mean LHRH levels of the
MK801 plus AS GAD67 treatment were not different from that of the MK801
treatment in prepubertal (Fig. 4, A and C) and pubertal monkeys (Fig. 4, B and D). However, LHRH release in prepubertal monkeys treated with
MK801 plus AS GAD67 (Fig. 4A) was significantly (P <
0.01) lower than in prepubertal monkeys treated with AS GAD67 alone
(Fig. 2A). Similarly, LHRH release in the pubertal monkeys treated with
MK801 plus AS GAD67 (Fig. 4B) was lower (P < 0.01)
than in pubertal monkeys treated with AS GAD67 alone (Fig. 2B).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In Study I, we observed that AS GAD67 stimulated LHRH release in pubertal as well as prepubertal monkeys. The effects of AS GAD67 on LHRH increase in prepubertal monkeys in this study started earlier and lasted longer than that observed in a previous study conducted in our laboratory (8). It is unclear why this difference occurred because the infusion protocol was essentially similar, except that the period of AS GAD67 infusion was 1 h shorter in this study than in the previous study. Nonetheless, the LHRH increase induced by AS GAD67 in this study is consistent with what we reported previously (8). In our previous study, we also found with Western blot analysis that AS GAD67 reduced GAD67 protein (8). Preliminary data further suggest that GABA levels decreased after AS GAD67 infusion (26). Therefore, infusion of AS GAD67 into the S-ME probably interfered with GAD67 synthesis, effectively reducing GABA release.
In pubertal monkeys treated with AS GAD67, a significant LHRH increase occurred 1 h later than in prepubertal monkeys, and the amount of the LHRH increase induced by AS GAD67 infusion in pubertal monkeys was smaller than that in prepubertal monkeys. These results suggest that there is an age-dependent difference in LHRH increase in response to AS GAD67. Although whether the presence of ovarian steroids in pubertal monkeys is due to the smaller LHRH response to AS GAD67 remains to be determined, the data can be interpreted to mean that GABA inhibition is considerably reduced in pubertal monkeys when compared with prepubertal monkeys. This view is supported by the fact that GABA levels in the S-ME of early and midpubertal monkeys were lower than those in prepubertal monkeys (7) and that the bicuculline-induced LHRH increase was much smaller in pubertal monkeys than in prepubertal monkeys (7). Therefore, inhibition of LHRH release by GABA in the S-ME "weakens" at the onset of puberty, but it remains even after the initiation of puberty.
In Study II we found that the AS GAD67-induced increase in LHRH release was suppressed by the NMDA receptor blocker, MK801. The results indicate that the AS GAD67-induced LHRH increase is not only due to the reduction of GABA tone in the S-ME, but also an increase in glutamate tone in the S-ME. In fact, preliminary data from our laboratory (26) suggest that glutamate increases following the decrease in GABA with treatment of AS GAD67. There are several explanations for the reduction of GABA tone resulting in the increase in glutamate tone. First, the developmental reduction of GABA release results in an increase in glutamate release by a presynaptic mechanism. This possibility is supported by an observation in monkeys that the perikarya of LHRH neurons are directly innervated by glutamate neurons, not GABA neurons, but glutamate neurons are innervated by GABA neurons (27). Second, the reduction of GABAergic input may allow an increase in the relative strength of excitatory glutamatergic input to LHRH neuroterminals, via a nonsynaptic mechanism, such as by a volume transmission (28). It has been shown that glutamate neuroterminals abut LHRH neuroterminals in the ME of rats (29), and nonsynaptic transmission could be mediated by nitric oxide (30, 31). Third, developmental reduction of GADs may lead to the accumulation of metabolic glutamate in GABA neurons because glutamate is a major precursor for GABA synthesis. Accumulated glutamate could be transported out of the cell resulting in excitation of the postsynaptic membrane. In this case, glutamate would not be released by Ca2+-dependent vesicular exocytosis, but would be released by a mechanism involving a Na+-dependent glutamate transporter. Such mechanisms have been reported in other types of neurons (32). Finally, a small elevation of estradiol, as a consequence of an increase in LHRH release due to GABA reduction, may increase glutamate release as well as receptor sensitivity to glutamate/NMDA, which in turn further increases glutamate tone.
It has been reported that GABA is inhibitory to LHRH and LH release in adult rats (33, 34, 35, 36, 37), whereas GABA is stimulatory in juvenile rats (38, 39). Moreover, Moguilevsky and his colleagues (40) reported that 1) GABA agonists (muscimol for GABAA and baclofen for GABAB) stimulated glutamate release as well as LHRH release in prepubertal male rats, but they inhibited both glutamate and LHRH release in adults, and 2) GABA antagonists (bicuculline for GABAA and phaclofen for GABAB) inhibited glutamate release as well as LHRH release in prepubertal male rats, whereas they stimulated both LHRH and glutamate release in adults. For the explanation of this paradoxical effect of GABA on LHRH release during sexual development, Bourguignon and his colleagues (41) postulate a reciprocal innervation between GABAergic and glutamatergic neurons. That is, during the juvenile period, inhibitory GABA neurons suppress glutamate neurons, which control LHRH neurons as well as GABA neurons, whereas in adults, reduction of GABA inhibition to glutamate neurons occurs, resulting in an increase in LHRH release.
The mechanism initiating puberty in rodents, represented by the studies in rats, appears to differ from that in primates. First, in monkeys, castration induces an elevation of gonadotropin release during the neonatal period and after the onset of puberty, but not during the juvenile period before the onset of puberty (42, 43), whereas in rats the castration-induced elevation of gonadotropin release occurs from the neonatal period throughout life (12). Second, NMDA-induced precocious puberty in monkeys does not lead to normal reproductive cycles as adults after cessation of the NMDA infusion (22), whereas in rats NMDA-induced precocious puberty continues with ovulatory cycles (21). Third, in primates there is a tonic GABA inhibition on LHRH release during the juvenile period, which is expressed by high GABA levels in the S-ME and an enhanced stimulatory effect of bicuculline on LHRH release (7). Moreover, as observed in this study, in primates the reduction of GABA inhibition appears to allow the activation of the excitatory glutamatergic system, which further contributes to increase LHRH release. In contrast, in rats comparable tonic central inhibition may not exist because bicuculline is inhibitory to LHRH release in the juvenile stage, and this bicuculline effect is reversed during the pubertal stage (40, 41). Thus, establishment of glutamatergic and other facilitatory neuronal systems may be more important for the onset of puberty in rats. Nonetheless, Bourguignon and colleagues (44) recently reported that treatment of an 11-month-old child who exhibited severe epileptic seizures and precocious puberty with the GABA agonists loreclezole and vigabatrin regressed all signs of precocious puberty, as well as seizure attacks, indicating that tonic GABA inhibition plays a key role in low levels of LHRH release before the onset of puberty in primates.
In summary, there is a tonic GABA inhibition of LHRH release before the onset of puberty in primates. At the onset of puberty, GABA inhibition declines, but is not completely removed. The reduction of GABA inhibition appears to be followed by a concurrent increase in glutamate tone. Subsequently, norepinephrine and neuropeptide Y neurons may also contribute to the progress of puberty (45, 46, 47). Because GAD is the enzyme controlling GABA synthesis, GAD may play an important role in the onset and progress of puberty.
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Acknowledgments |
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Footnotes |
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2 Present address: State University of New York-Morrisville,
Morrisville, New York 13408.
3 Present address: University of Tokyo, School of Veterinary
Medicine, Tokyo, Japan.
Received June 10, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-Aminobutyric acid is an inhibitory neurotransmitter restricting the
release of luteinizing hormone-releasing hormone before the onset of
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, P < 0.05 and 
