Number Of Parvalbumin-positive Cells Research Articles

Interneuron Development Is Disrupted in Preterm Brains With Diffuse White Matter Injury: Observations in Mouse and Human.

Preterm brain injury, occurring in approximately 30% of infants born <32 weeks gestational age, is associated with an increased risk of neurodevelopmental disorders, such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). The mechanism of gray matter injury in preterm born children is unclear and likely to be multifactorial; however, inflammation, a high predictor of poor outcome in preterm infants, has been associated with disrupted interneuron maturation in a number of animal models. Interneurons are important for regulating normal brain development, and disruption in interneuron development, and the downstream effects of this, has been implicated in the etiology of neurodevelopmental disorders. Here, we utilize postmortem tissue from human preterm cases with or without diffuse white matter injury (WMI; PMA range: 23+2 to 28+1 for non-WMI group, 26+6 to 30+0 for WMI group, p = 0.002) and a model of inflammation-induced preterm diffuse white matter injury (i.p. IL-1β, b.d., 10 μg/kg/injection in male CD1 mice from P1–5). Data from human preterm infants show deficits in interneuron numbers in the cortex and delayed growth of neuronal arbors at this early stage of development. In the mouse, significant reduction in the number of parvalbumin-positive interneurons was observed from postnatal day (P) 10. This decrease in parvalbumin neuron number was largely rectified by P40, though there was a significantly smaller number of parvalbumin positive cells associated with perineuronal nets in the upper cortical layers. Together, these data suggest that inflammation in the preterm brain may be a contributor to injury of specific interneuron in the cortical gray matter. This may represent a potential target for postnatal therapy to reduce the incidence and/or severity of neurodevelopmental disorders in preterm infants.

Age-related neurochemical changes in the rhesus macaque inferior colliculus.

Age-related hearing loss (ARHL) is marked by audiometric hearing deficits that propagate along the auditory pathway. Neurochemical changes as a function of aging have also been identified in neurons along the auditory pathway in both rodents and carnivores, however, very little is known about how these neurochemicals change in the non-human primate. To examine how these compensatory neurochemical changes relate to normal aging and audiometric sensitivity along the auditory pathway, we collected auditory brainstem responses (ABRs) and brain specimens from seven rhesus monkeys spanning in age from 15 to 35 years old, and examined the relationship between click evoked ABR thresholds and the ABR evoked pure tone average (PTA) and changes in the number of parvalbumin and NADPH-diaphorase positive cells in the auditory midbrain. We found that the number of parvalbumin positive cells in the central nucleus and the surrounding cortex regions of the inferior colliculus were strongly correlated with advancing age and ABR PTA. We also found that the numbers of NADPHd positive cells in these same regions were not associated with normal aging or changes in the ABR thresholds. These findings suggest that the auditory midbrain undergoes an up-regulation of parvalbumin expressing neurons with aging that is related to changes in the processing of frequencies across the audiometric range.

Rac1 and Rac3 GTPases Control Synergistically the Development of Cortical and Hippocampal GABAergic Interneurons

The intracellular mechanisms driving postmitotic development of cortical γ-aminobutyric acid (GABA)ergic interneurons are poorly understood. We have addressed the function of Rac GTPases in cortical and hippocampal interneuron development. Developing neurons express both Rac1 and Rac3. Previous work has shown that Rac1 ablation does not affect the development of migrating cortical interneurons. Analysis of mice with double deletion of Rac1 and Rac3 shows that these GTPases are required during postmitotic interneuron development. The number of parvalbumin-positive cells was affected in the hippocampus and cortex of double knockout mice. Rac depletion also influences the maturation of interneurons that reach their destination, with reduction of inhibitory synapses in both hippocampal CA1 and cortical pyramidal cells. The decreased number of cortical migrating interneurons and their altered morphology indicate a role of Rac1 and Rac3 in regulating the motility of cortical interneurons, thus interfering with their final localization. While electrophysiological passive and active properties of pyramidal neurons including membrane capacity, resting potential, and spike amplitude and duration were normal, these cells showed reduced spontaneous inhibitory currents and increased excitability. Our results show that Rac1 and Rac3 contribute synergistically to postmitotic development of specific populations of GABAergic cells, suggesting that these proteins regulate their migration and differentiation.

Ferulic acid attenuates the focal cerebral ischemic injury-induced decrease in parvalbumin expression

Ferulic acid exerts a neuroprotective effect through its anti-oxidant and anti-inflammation properties. Parvalbumin has calcium buffering capacity and protects neuronal cells from cytotoxic Ca2+ overload. This study investigated whether ferulic acid regulates parvalbumin expression in cerebral ischemia and glutamate toxicity-induced neuronal cell death. Male Sprague-Dawley rats were immediately treated with vehicle or ferulic acid (100mg/kg, i.v.) after middle cerebral artery occlusion (MCAO), and cerebral cortex tissues were collected 24h after MCAO. A proteomics approach elucidated the decrease of parvalbumin in MCAO-operated animals, and ferulic acid treatment attenuated the injury-induced decrease in parvalbumin expression. Moreover, RT-PCR and Western blot analyses clearly showed that ferulic acid treatment prevents the injury-induced decrease in parvalbumin levels. The number of parvalbumin-positive cells also decreased in MCAO-operated animals, and ferulic acid attenuated this injury-induced decrease in parvalbumin-positive cells. In cultured hippocampal cells, glutamate toxicity significantly increased the intracellular Ca2+ concentration, whereas this increase in Ca2+ levels was inhibited by ferulic acid treatment. In addition, ferulic acid treatment attenuated the glutamate exposure-induced decrease in parvalbumin levels. These results suggest that ferulic acid exerts a neuroprotective effect by attenuating the injury-induced decrease of parvalbumin and modulating intracellular Ca2+ levels.

Similar distribution changes of GABAergic interneuron subpopulations in contrast to the different impact on neurogenesis between developmental and adult-stage hypothyroidism in the hippocampal dentate gyrus in rats

Hypothyroidism affects neurogenesis. The present study was performed to clarify the sensitivity of neurogenesis-related cellular responses in the hippocampal dentate gyrus between developmental and adult-stage hypothyroidism. An exposure study of methimazole (MMI) as an anti-thyroid agent at 0, 50, 200 ppm in the drinking water was performed using pregnant rats from gestation day 10 to postnatal day (PND) 21 (developmental hypothyroidism) and adult male rats by setting an identical exposure period from PND 46 through to PND 77 (adult-stage hypothyroidism). Offspring with developmental hypothyroidism were killed at PND 21 or PND 77, and animals with adult-stage hypothyroidism were killed at PND 77. Proliferation and apoptosis were unchanged in the dentate subgranular zone by either developmental or adult-stage hypothyroidism. With regard to precursor granule cells, a sustained reduction of paired box 6-positive stem or early progenitor cells and a transient reduction of doublecortin-positive late-stage progenitor cells were observed after developmental hypothyroidism with MMI at 50 and 200 ppm. These cells were unchanged by adult-stage hypothyroidism. With regard to γ-aminobutyric acid (GABA) ergic interneuron subpopulations in the dentate hilus, the number of parvalbumin-positive cells was decreased and the number of calretinin-positive cells was increased after both developmental and adult-stage hypothyroidism with MMI at 50 and 200 ppm. Fluctuations in GABAergic interneuron numbers with developmental hypothyroidism continued through to PND 77 with 200 ppm MMI. Considering the roles of GABAergic interneuron subpopulations in neurogenesis and neuronal differentiation, subpopulation changes in GABAergic interneurons by hypothyroidism may be the signature of aberrant neurogenesis even at the adult stage.

Ginkgo bilobaextract (EGb 761) prevents the ischemic brain injury-induced decrease in parvalbumin expression

Ginkgo biloba extract (EGb 761) exerts a neuroprotective effect against ischemic brain injury through an anti-apoptotic mechanism. Parvalbumin is a calcium buffering protein that plays an important role in modulating intracellular calcium concentration and regulating apoptotic cell death. The aim of this study was to investigate whether EGb 761 affects parvalbumin expression in cerebral ischemic injury. Adult male Sprague-Dawley rats were treated with vehicle or EGb 761 (100 mg/kg) prior to middle cerebral artery occlusion (MCAO) and cerebral cortex tissues were collected 24 h after MCAO. A proteomic approach revealed a reduction in parvalbumin expression in the vehicle-treated animals, whereas EGb 761 pretreatment attenuates the ischemic injury-induced decrease in parvalbumin expression. RT-PCR and Western blot analyses clearly confirmed the fact that EGb 761 prevents the injury-induced decrease in parvalbumin. Moreover, the results of immunohistochemical staining showed that the number of parvalbumin-positive cells was lower in vehicle-treated animals than in sham-operated animals, and EGb 761 averted this decrease. Thus, these results suggest that the maintenance of parvalbumin expression is associated with the neuroprotective function of EGb 761 against neuronal damage induced by ischemia.

Neonatal Phencyclidine Treatment in Mice Induces Behavioral, Histological and Neurochemical Abnormalities in Adulthood

We investigated the involvement of glutamic acid in neural development by injecting phencyclidine (PCP) into neonatal ICR mice. Neonatal mice were injected with PCP at 10 mg/kg or saline on postnatal days 7, 9 and 11, and their behavioral, anatomical and neurochemical changes were analyzed in adulthood. PCP-treated mice exhibited an increase in PCP-induced hyperactivity and impairments of spatial working memory and social interaction behavior. The impairment of social interaction behavior was significantly reversed by administration of clozapine, D-cycloserine, flumazenil, or SHC50911, a gamma-aminobutyrate B (GABA(B)) receptor antagonist. A decrease in the number of parvalbumin-positive cells and spine density in the frontal cortex, nucleus accumbens and hippocampus were evident in the brains of PCP-treated mice. Measurement of brain monoamine and their metabolite contents in adulthood indicated brain area-dependent and neurotransmitter-specific changes in monoamine metabolism. These findings suggest that neonatal treatment with PCP in mice leads to enhanced sensitivity to PCP and impairment of spatial working memory and social interaction behaviors in adulthood, which may be associated with reduced spine density and GABAergic interneurons and changes in monoamine metabolism. Furthermore, pharmacologic experiments suggest the potential applicability of neonatally PCP-treated mice as a useful animal model for new antipsychotic drug screening.

Evolution of morphological and histochemical changes in the adult cat cuneate nucleus following forelimb denervation.

Morphological and histochemical changes were studied in the ipsilateral cuneate nucleus between one and 52 weeks after forelimb denervation in adult cats. The deafferented nucleus and neighboring fasciculus were noticeably reduced in size within four weeks and decreased further by 13 weeks. The intensity of acetylcholinesterase staining decreased within one week and was further reduced one month after nerve transections. This reduction in acetylcholinesterase staining was transient, approaching control levels within one year. Parvalbumin immunostaining was also altered by the nerve transections; on the deafferented side, the neuropil staining in the cuneate nucleus and fasciculus decreased, but the number of parvalbumin-positive cells was consistently greater than in the contralateral side. These cell counts returned to normal levels within one year. One month after the injury, cytochrome oxidase activity was reduced. This reduction persisted and was even more apparent after one year. In parallel, the cell clusters of the nucleus became progressively less distinct. These observations in an adult mammal indicate that peripheral nerve injury imposes molecular and morphological changes on second-order sensory neurons which evolve differentially with time. Although some changes developed rapidly after deafferentation, the onset of others was slower; and whereas some seemed irreversible, others eventually regressed. Taken together with the functional studies of others, these findings suggest that early molecular changes observed in cuneate neurons reflect adaptive reactions to lesion-induced alterations in afferent activity. Permanent deprivation of the normal input, however, would eventually lead to chronic, and perhaps irreversible, degenerative changes.