Development of GABA and calcium binding proteins immunoreactivity in the rat hippocampus following neonatal anoxia

doi:10.1016/0304-3940(96)12733-6

Neuroscience Letters

Volume 211, Issue 2, 21 June 1996, Pages 93-96

https://doi.org/10.1016/0304-3940(96)12733-6 Get rights and content

Abstract

The consequences of neonatal anoxia (N₂ 100% for 25 min at 30 h after birth) on the rat hippocampus were studied 7–60 days postnatally with immunocytochemistry for γ-aminobutyric acid (GABA), parvalbumin (PV) and calbindin-D28k (CB). In both sham-treated and anoxic rats, GABA immunoreactivity presented a mature expression since early stages, while PV and CB immunoreactivity showed a major postnatal development. In anoxic animals, a significant reduction in the number of hippocampal GABA-immunoreactive neurons was observed at all time-points analysed, a transitory effect on PV immunoreactivity was seen at P7 and P21, while no modifications in the number of CEI-immunoreactive neurons could be found. Thus, selective vulnerability of GABA-containing neurons and relative resistance of neurons in which PV or CB immunoreactivity is present or is expressed later, occur in the hippocampus after neonatal anoxia. The role of calcium binding proteins (CBP) in nerve cell protection is discussed.

References (22)

R.E. Burke et al.
Relative loss of the striatal striosome compartment, defined by calbindin-D28k immunostaining, following developmental hypoxic-ischemic injury
Neuroscience
(1993)
M.R. Celio
Calbindin D-28k and parvalburnin in the rat nervous system
Neuroscience
(1990)
M.E. Dell'Anna et al.
Neonatal anoxia induces transitory hyperactivity, permanent spatial memory deficits and CAI cell density reduction in developing rats
Behav. Brain Res.
(1991)
M.E. Dell'Anna et al.
Transient changes in fos and GFAp immunoreactivity precede neuronal cell loss in the rat hippocampus following neonatal anoxia
Exp. Neurol.
(1995)
M. Erecinska et al.
Neurotransmitter amino acids in the CNS. 1. Regional changes in amino acid levels in rat brain during ischemia and reperfusion
Brain Res.
(1984)
T. Fukuda et al.
Persistent degenerative state of non-pyramidal neurons in the CAI region of the gerbil hippocampus following transient forebrain ischemia
Neuroscience
(1993)
J.H. Goodman et al.
Calbindin-D28k immunoreactivity and selective vulnerability to ischemia in the dentate gyrus of the developing rat
Brain Res.
(1993)
K.M. Harris et al.
Evidence of late development of inhibition in area CAI of the rat hippocampus
Brain Res.
(1983)
F.-F. Johansen et al.
Short-term changes of parvalburnin and calbindin immunoreactivity in the rat hippocampus following cerebral ischemia
Neurosci. Lett.
(1990)
T. Kosaka et al.
GABAergic neurons containing the Ca⁺⁺-binding protein parvalburnin in the rat hippocampus and dentate gyros
Brain Res.
(1987)

J.M. Lauder et al.

Prenatal ontogeny of the GABAergic system in the rat brain: an immunocytochemical study

Neuroscience

(1986)

Cited by (38)

Animal models for neonatal brain injury induced by hypoxic ischemic conditions in rodents
2020, Experimental Neurology
Citation Excerpt :
This model is reported to produce transient and persistent physiological and behavioural changes. Brief reactive astrocytosis occurs in P7 pups (Dell’Anna et al., 1995), as well as a temporary decrease in parvalbumin immunoreactivity observed between P7 and P21 (Dell’Anna et al., 1996; Iuvone et al., 1996). More persistent changes observed include a decrease in CA1 neurons (Dell’Anna et al., 1995) and hippocampal GABA-immunoreactive neurons (Dell’Anna et al., 1996).
Neonatal hypoxia-ischemia and resulting encephalopathies are of significant concern. Intrapartum asphyxia is a leading cause of neonatal death globally. Among surviving infants, there remains a high incidence of hypoxic-ischemic encephalopathy due to neonatal hypoxic-ischemic brain injury, manifesting as mild conditions including attention deficit hyperactivity disorder, and debilitating disorders such as cerebral palsy. Various animal models of neonatal hypoxic brain injury have been implemented to explore cellular and molecular mechanisms, assess the potential of novel therapeutic strategies, and characterize the functional and behavioural correlates of injury. Each of the animal models has individual advantages and limitations. The present review looks at several widely-used and alternative rodent models of neonatal hypoxia and hypoxia-ischemia; it highlights their strengths and limitations, and their potential for continued and improved use.
Impaired Organization of GABAergic Neurons Following Prenatal Hypoxia
2018, Neuroscience
Citation Excerpt :
Neuron populations that are particularly affected by hypoxic insult are the GABAergic interneurons. In response to perinatal anoxia, the density of GABA immunoreactive (IR) neurons in the cerebral cortex and hippocampus decreased seven days after insult, a condition that was maintained into adulthood (Dell'Anna et al., 1996). Reduced density of the sub-population of GABAergic neurons expressing the calcium-binding protein calbindin (CB) in the cortex was observed 20 days after hypoxic insult on embryonic day 17 (E17) (Louzoun-Kaplan et al., 2008).
Several conditions related to the intrauterine environment are associated with neuropsychiatric conditions in later life. In humans, approximately 2% of infants are exposed to perinatal hypoxia–ischemia or prolonged anoxic insult, a condition to which very low birth weight preterm infants exhibit the highest susceptibility. Analyses of postmortem tissue link some presentations of these conditions to changes in GABA pathway functionality in the brains of affected subjects. Using animal models of early-life hypoxia–ischemia, losses of particular interneuron populations were reported. We hypothesize that the origin of GABAergic cell loss is in the mispositioning of neurons during the formation of the cerebral cortex. Here we report that in C57 black mice exposed to hypoxic conditions (9% O₂; 3% CO₂), 22–26% of cell loss was detected in the cortical plate as early as four days after the hypoxic event. Moreover, the surviving cells failed to populate the proper layers in the developing cortex. Differential sensitivities were observed in neurons that originated from different germinal zones. A significant effect of GABAergic cell location along the anterior–posterior and medio-lateral axes on neuron sensitivity to hypoxia was detected. Finally, changes in guidance molecules in the developing cortex, including increases in hypoxia-inducible factor 1-alpha levels and intracellular distribution, decreases in reelin levels in the cortical plate and altered organization of radial glia, were observed. These changes in the molecular landscape of the immediate environment of the immature neurons may contribute to the observed outcomes in neuronal migration to, and establishment in, the correct cortical layers. We suggest that the interneuron loss may be related to these early events.
Consequences of perinatal hypoxia in developing brain: Changes in GABA transporter functioning in cortical, hippocampal and thalamic rat nerve terminals
2017, International Journal of Developmental Neuroscience
Citation Excerpt :
We revealed a long-lasting increase in the ambient level of [3H]GABA in the cortical and hippocampal nerve terminals, whereas the thalamic ones were less vulnerable to perinatal hypoxia (Pozdnyakova et al., 2011). A particular vulnerability of GABAergic neurons (Dell’Anna et al., 1996; Robinson et al., 2006), a long-lasting decrease of thresholds to convulsants in adult rats that underwent hypoxia at early age and age – dependent long-term changes in seizure excitability and neurobehavior of the rats following hypoxia were demonstrated (Van De Berg et al., 2003; Jensen and Wang, 1996; Jensen, 2009; Rakhade et al., 2011). The cortical expressions of GAT-1 and GAT-3 were investigated in rats with transient focal ischemia (Melone et al., 2003), and it was revealed that expression of GAT-1 and GAT-3 was selectively affected under this conditions.
Perinatal hypoxia leads to behavioral abnormalities, cognitive disabilities, and epilepsy resulting from alterations in neurodevelopment, maturation and construction of the network. Considering a particular role of γ-aminobutyric acid (GABA) for an immature brain, we analysed transporter-mediated [³H]GABA uptake in the cortical, hippocampal and thalamic nerve terminals isolated from rats of different age in the control and after perinatal hypoxia. The state of hypoxia was induced by exposure of rats at the age of 10 postnatal days (pd) (that corresponds approximately to the time of birth in humans) to a respiratory medium with low O₂ content (4% O₂ and 96%N₂) for 12 min (up to the initiation of clonico-tonic seizures). Here, we found that the initial rate of [³Н]GABA uptake was higher in the young rats (pd 17–19) as compared to the older ones (pd 24–26, 38–40 and 66–73) in both control and hypoxia groups. It decreased abruptly by 50% in the thalamus and by 25% in the cortex for the period from pd 17–19 to pd 66–73. In the hippocampus, a decrease in the rate during the same time interval was 25%. Exposure to hypoxia had no effect on the intensity of [³Н]GABA uptake by the cortical and thalamic nerve terminals, but caused a significant age-dependent attenuation (by 35%) of the uptake intensity in the hippocampal ones. Significant age-dependent hypoxia-independent decrease in [³Н]GABA uptake with step-like dynamics of changes was shown in the thalamus and cortex. Gradual age-dependent hypoxia-dependent decrease in [³Н]GABA uptake was revealed in the hippocampus, and so a particular vulnerability of the latest structure to hypoxia as compared to the cortex and thalamus was revealed.
Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology?
2016, Schizophrenia Research
Accumulating evidence points to altered GABAergic parvalbumin-expressing interneurons and impaired myelin/axonal integrity in schizophrenia. Both findings could be due to abnormal neurodevelopmental trajectories, affecting local neuronal networks and long-range synchrony and leading to cognitive deficits. In this review, we present data from animal models demonstrating that redox dysregulation, neuroinflammation and/or NMDAR hypofunction (as observed in patients) impairs the normal development of both parvalbumin interneurons and oligodendrocytes. These observations suggest that a dysregulation of the redox, neuroimmune, and glutamatergic systems due to genetic and early-life environmental risk factors could contribute to the anomalies of parvalbumin interneurons and white matter in schizophrenia, ultimately impacting cognition, social competence, and affective behavior via abnormal function of micro- and macrocircuits. Moreover, we propose that the redox, neuroimmune, and glutamatergic systems form a “central hub” where an imbalance within any of these “hub” systems leads to similar anomalies of parvalbumin interneurons and oligodendrocytes due to the tight and reciprocal interactions that exist among these systems. A combination of vulnerabilities for a dysregulation within more than one of these systems may be particularly deleterious. For these reasons, molecules, such as N-acetylcysteine, that possess antioxidant and anti-inflammatory properties and can also regulate glutamatergic transmission are promising tools for prevention in ultra-high risk patients or for early intervention therapy during the first stages of the disease.
The primate seahorse rhythm
2015, Brain Research
Citation Excerpt :
On the other hand, at the beginning of the day (ZT 0), there was an increase of CR-IR in the granular and CB-IR in the polymorphic layers of the hippocampus. CB is one of the major CaBPs that exhibits other neuromodulatory functions such as synaptic plasticity, spatial learning, and memory functions (Dell’Anna et al., 1996; Stefanits et al., 2014). Although there is rhythmicity in the CB expression in the SCN (Menet et al., 2003) and CR expression in the retina (Witkovsky et al., 2003), possible variations in this protein in hippocampus had not been studied yet.
The main Zeitgeber, the day–night cycle, synchronizes the central oscillator which determines behaviors rhythms as sleep–wake behavior, body temperature, the regulation of hormone secretion, and the acquisition and processing of memory. Thus, actions such as acquisition, consolidation, and retrieval performed in the hippocampus are modulated by the circadian system and show a varied dependence on light and dark. To investigate changes in the hippocampus’ cellular mechanism invoked by the day and night in a diurnal primate, this study analyzed the expression of PER2 and the calcium binding proteins (CaBPs) calbindin, calretinin and parvalbumin in the hippocampus of Sapajus apella, a diurnal primate, at two different time points, one during the day and one during the dark phase. The PER2 protein expression peaked at night in the antiphase described for the suprachiasmatic nucleus (SCN) of the same primate, indicating that hippocampal cells can present independent rhythmicity. This hippocampal rhythm was similar to that presented by diurnal but not nocturnal rodents. The CaBPs immunoreactivity also showed day/night variations in the cell number and in the cell morphology. Our findings provide evidence for the claim that the circadian regulation in the hippocampus may involve rhythms of PER2 and CaBPs expression that may contribute to the adaptation of this species in events and activities relevant to the respective periods.
Early-life insults impair parvalbumin interneurons via oxidative stress: Reversal by N-acetylcysteine
2013, Biological Psychiatry
A hallmark of the pathophysiology of schizophrenia is a dysfunction of parvalbumin-expressing fast-spiking interneurons, which are essential for the coordination of neuronal synchrony during sensory and cognitive processing. Oxidative stress as observed in schizophrenia affects parvalbumin interneurons. However, it is unknown whether the deleterious effect of oxidative stress is particularly prevalent during specific developmental time windows.
We used mice with impaired synthesis of glutathione (Gclm knockout [KO] mice) to investigate the effect of redox dysregulation and additional insults applied at various periods of postnatal development on maturation and long-term integrity of parvalbumin interneurons in the anterior cingulate cortex.
A redox dysregulation, as in Gclm KO mice, renders parvalbumin interneurons but not calbindin or calretinin interneurons vulnerable and prone to exhibit oxidative stress. A glutathione deficit delays maturation of parvalbumin interneurons, including their perineuronal net. Moreover, an additional oxidative challenge in preweaning or pubertal but not in young adult Gclm KO mice reduces the number of parvalbumin-immunoreactive interneurons. This effect persists into adulthood and can be prevented with the antioxidant N-acetylcysteine.
In Gclm KO mice, early-life insults inducing oxidative stress are detrimental to immature parvalbumin interneurons and have long-term consequences. In analogy, individuals carrying genetic risks to redox dysregulation would be potentially vulnerable to early-life environmental insults, during the maturation of parvalbumin interneurons. Our data support the need to develop novel therapeutic approaches based on antioxidant and redox regulator compounds such as N-acetylcysteine, which could be used preventively in young at-risk subjects.

View all citing articles on Scopus

View full text

Development of GABA and calcium binding proteins immunoreactivity in the rat hippocampus following neonatal anoxia

Abstract

Neuroscience

Neuroscience

Behav. Brain Res.

Exp. Neurol.

Brain Res.

Neuroscience

Brain Res.

Brain Res.

Neurosci. Lett.

Brain Res.

Neuroscience