[Prenatal alcohol exposure as an etiological factor in neuropsychiatric diseases of childhood, adolescence and adulthood]. / La exposición prenatal al alcohol como factor etiológico de enfermedades neuropsiquiátricas de la infancia, adolescencia y adultez.

In Argentina, prenatal alcohol exposure (PAE) is an almost neglected condition as an important etiological factor for the induction of a wide spectrum of neuropsychiatric diseases that may appear during childhood, adolescence or adulthood. Children born to alcoholic mothers may show a spectrum of diseases ranging from an apparent normality to a profound mental retardation, passing through epilepsy, attention deficit disorders with or without hyperactivity, autism and pervasive developmental disorders, and different types of learning disorders. When adolescents, they may develop different kinds of personality disorders and substance abuse disorders. Finally, in adulthood, they may suffer from different types of affective and psychotic disorders, among others. A great number of those children may not develop their full mental and social potentiality as free individuals. They usually have diverse types of cognitive, attentional, mnemonic and affective impairments. Not infrequently, they engage in antisocial behaviors, have school or work troubles. In this work, I review the present clinical classifications of the disorders emerging from a PAE and the several neuropsychiatric diseases that can be induced by them, in order to call attention to the Argentinian neuropsychiatric community about the increasingly, although underdiagnosed, frequency of these disorders in our country.

Neuronal cytoskeleton and synaptic densities are altered after a chronic treatment with the cannabinoid receptor agonist WIN 55,212-2.

Cannabinoid CB1 receptors are the most abundant G-protein-coupled receptors in the brain. Its presynaptic location suggests a role for cannabinoids in modulating the release of neurotransmitters from axon terminals by retrograde signaling. The neuroprotective effects of cannabinoid agonists in animal models of ischemia, seizures, hypoxia, Multiple Sclerosis, Huntington and Parkinson disease have been demonstrated in several reports. The proposed mechanism for the neuroprotection ranges from antioxidant effects, reduction of microglial activation and anti-inflammatory reaction to receptor-mediated reduction of glutamate release. In the present work, we analyzed the morphological changes induced by a chronic treatment with the synthetic cannabinoid receptor agonist, WIN 55,212-2, in four brain regions where the CB1 cannabinoid receptor is present in high density: the CA1 hippocampal area, corpus striatum, cerebellum and frontal cortex. After a twice-daily treatment for 14 days with the cannabinoid receptor agonist (3 mg/kg sc, each dose) to male Wistar rats (150-170 g), the expression of neurofilaments (Nf-160 and Nf-200), microtubule-associated protein-2 (MAP-2), synaptophysin (Syn) and glial fibrillary acidic protein (GFAP) was studied by immunohistochemistry and digital image analysis. Ultrastructural study of the synapses was done using electron microscopy. After the treatment, a significant increase in the expression of neuronal cytoskeletal proteins (Nf-160, Nf-200, MAP-2) was observed, but we did not find changes in the expression of GFAP, the main astroglial cytoskeletal protein. In cerebellum, there was an increase in Syn expression and in the number of synaptic vesicles, while, in the hippocampus, an increase in the Syn expression and in the thickness of the postsynaptic densities was observed. The results obtained from these studies provide evidences on the absence of astroglial reaction and a sprouting phenomena induced by the WIN treatment that might be a key contributor to the long-term neuroprotective effects observed after cannabinoid treatments in different models of central nervous system (CNS) injury reported in the literature.

Alcohol exposure during adulthood induces neuronal and astroglial alterations in the hippocampal CA-1 area.

Ethanol (ETOH) exposure can result in neuronal damage. Astrocytes are morphologic and functionally related to neurons, and astrocyte-neuron interactions provide strategic sites for the actions of many chemical compounds. The aim of the present work was to study the morphologic alterations of glial cells and neurons on the hippocampus after long-term ETOH exposure using GFAP and S-100 beta protein, neurofilaments of 200 kDa (Nf200), MAP2, and serotonin transporter (5HT-T) immunocytochemical staining. Adult Wistar male rats (200-250 g) were orally exposed to ETOH (6.6% v/v ad libitum) for 6 weeks. Control rats received water ad libitum. Brain sections from control and exposed rats were processed by immunocytochemistry. After ETOH exposure we observed in the CA1 area of the hippocampus: (1) an important astroglial reaction evidenced by the presence of GFAP(+) reactive astrocytes; (2) an increase in S-100 beta immunostaining in astroglial cells; and (3) a decrease in Nf200, 5HT-T, and MAP2 immunoreactivity. The current study provides evidence that long-term ETOH exposure induces alterations in the neuronal cytoskeleton and an astroglial reaction, which is a common response to brain injury and may promote functional recovery of the nervous system, as by the release of glial-derived trophic factors (such as S-100 beta) that promote cell survival and neurite growth.

Effects of chronic maternal ethanol exposure on hippocampal and striatal morphology in offspring.

Astrocytes and serotoninergic neurons play a role in central nervous system (CNS) development, probably through serotonin (5HT) stimulation of the glial 5HT(1A) receptor. Activation of 5HT(1A) receptors causes the release of S-100 beta, a glial derived growth factor. In vitro, astrocytes are profoundly altered by chronic maternal ethanol exposure (CMEE). CMEE is also associated with reduced 5HT brain levels and abnormal development of the serotoninergic system. In the present study we analyzed the hippocampal and striatal serotoninergic innervation and astroglial cells in the offspring of CMEE mothers. Female Wistar rats were orally exposed to ethanol 6.6% (v/v) ad libitum for 6 weeks before breeding and during gestation. After parturition, rat mothers continued receiving ethanol until pups reached 21 days old. The control group received water ad libitum. Rat offspring brains were processed by immunocytochemistry using antibodies directed to GFAP, serotonin transporter (5HTT), or S-100 beta protein. Hippocampus and striatum were studied by computer-assisted image analysis. Cell area of GFAP(+) astrocytes, surface of 5HTT(+) fibers per area unit, and relative optical density (ROD) of S-100 beta(+) astrocytes were measured and statistically processed. Our results show that astroglial GFAP was increased (astrocytes were hypertrophied) and 5HTT(+) fibers were increased in both the hippocampal CA-1 area and the striatum. On the other hand, S-100 beta ROD was increased only in the hippocampal CA-1 area but not in the striatum. The different response of the studied regions is an interesting result considering evidence of a close 5HT/astroglial relation during CNS development. These differences could be due to different gradients of development in the studied areas and/or different responses of those areas to the effect of maternal ethanol exposure since the first stages of embryonic development.

Altered neuron-glia interactions in a low, chronic prenatal ethanol exposure.

Serotoninergic neurons, astrocytes and nitrergic system play an important role in central nervous system (CNS) development. These systems are altered in prenatal ethanol exposure (PEE) but ethanol (EtOH) effects may be very diverse under different conditions. In this study, we analyzed morphologically two serotoninergic mesencephalic nuclei and three prosencephalic areas of serotoninergic innervation in a model of pre- and postnatal low-ethanol exposure. Female Wistar rats were orally exposed to EtOH 6.6% (v/v), ad libitum, for 6 weeks before mating and during gestation and lactation while control group received water ad libitum. Twenty-day-old offspring (P21) brains were processed and immunoreactivity (IR) using antibodies against tryptophan hydroxylase (TPH), 5-HT, 5-HT transporter (5HTT), glial fibrillary acidic protein (GFAP), S-100B protein, 200-kDa neurofilaments (Nf-200) and neuronal nitric oxide synthase (nNOS) was evaluated. Dorsal and median raphe nucleus (DRN and MRN), hippocampus (Hipp), striatum (Strt) and frontal cortex (FCx) were studied by computer-assisted image analysis. Relative optical density (ROD) of TPH-IR, 5-HT-IR and nNOS-IR neurons; cell area of GFAP-IR astrocytes; relative area of 5HTT-IR fibers and Nf-200-IR were evaluated. TPH-IR was increased in DRN and MRN and 5-HT-IR was increased only in MRN. 5-HTT-IR fibers and ROD of S-100B-IR astrocytes were increased in the three prosencephalic areas while GFAP-IR astrocytes were hypertrophied only in Hipp and FCx. Nf-200 expression was increased in Hipp and Strt and morphologically altered in the FCx. ROD of nNOS-IR neurons was increased in Strt and FCx but was not detected in Hipp. We have also detected morphological changes resembling accelerated development and maturation, and early aging. Considering the evidences of a close 5-HT-astroglial-NO relationship during CNS development the differential response of the studied regions is an interesting result that could be due to different gradients of development in the studied areas and/or different responses of those areas to the effects of a low pre- and postnatal ethanol exposure.

Effects of prenatal ethanol exposure on rat brain radial glia and neuroblast migration.

Prenatal ethanol exposure (PEE) induces morphologic and functional alterations in the developing central nervous system. The orderly migration of neuroblasts is a key process in the development of a layered structure such as the cerebral cortex (CC). From initial stages of corticogenesis, the transcription factor Pax6 is intensely expressed in neuroepithelial and radial glia cells (RGCs) and is involved in continual regulation of cell surface properties responsible for both cellular identity and radial migration. In the present work, one month before mating, during pregnancy and lactation, a group of female Wistar rats were fed a liquid diet with 5.9% (w/w) ethanol (EtOH), rendering moderate blood EtOH concentrations. Maternal gestational weight progression and fetal CC thickness were measured. CC from E12-P3 rats were examined for expression of vimentin, nestin, S-100b, Pax6 and doublecortin using immunohistochemical assays. RGCs expressing vimentin, nestin, S-100b and Pax6 had abnormal morphologies. The migration distance through the CC and the number of doublecortin-ir neuroblasts in germinative zones were decreased. We found significant morphologic defects on RGCs, a marked delay in neuronal migration, decreased numbers of neuroblasts, and decreased numbers of Pax6-ir cells in the CC as a consequence of exposure to ethanol during development. These observations suggest a sequence of toxic events that contribute to cortical dysplasia in offspring exposed to EtOH during gestation.

[Diagnostic criteria for fetal alcohol syndrome and fetal alcohol spectrum disorders]. / Criterios diagnósticos del síndrome alcohólico fetal y los trastornos del espectro del alcoholismo fetal.

Prenatal ethanol exposure, in our professional practice, is an almost neglected condition as an important etiological factor for the induction of a wide spectrum of neuropsychiatric diseases that may appear during childhood, adolescence or adulthood. Children born to alcoholic mothers may show a profound mental retardation ranging to an apparent normality, and extending through epilepsy, attention deficit disorders with or without hyperactivity, autism and pervasive developmental disorders, and different types of learning disorders. When adolescents, they may develop different kinds of personality disorders and substance abuse disorders. Finally, in adulthood, they may suffer from different types of affective and psychotic disorders, among others. A great number of those children may not develop their full mental and social potentiality as free individuals. They usually have diverse types of cognitive, attentional, mnemonic and affective impairments. Not infrequently, they engage in antisocial behaviors or have school or work troubles. In this work, the present clinical classifications and diagnostic criteria for the disorders emerging from a prenatal ethanol exposure are reviewed in order to call attention to the medical pediatric and neuropsychiatric community about the increasingly, although underdiagnosed, frequency of these disorders in our country.

Prenatal ethanol exposure reduces the expression of the transcriptional factor Pax6 in the developing rat brain.

Prenatal ethanol exposure (PEE) induces functional and structural disorders in the developing central nervous system (CNS). The relationship between radial glial cells (RGCs) and migrating neuroblasts is crucial for the establishment of normal CNS laminated structures. Pax6, a transcription factor involved in mammalian neuronal developmental processes, could be affected by PEE, as it is already known to occur in amphibians. From gestational day 10 to 18 (G10-G18), pregnant Wistar rats were subjected to an intraperitoneal injection of a daily ethanol (EtOH) 3.5 g/kg dose. Control pregnant rats received equivalent volumes of saline solution. Fetal weights and cerebral cortex thickness were significantly lower in G18 PEE than in control fetuses, and neural tube defects were found in the G18 PEE fetuses. Cortical expression of vimentin (an RGC cytoskeletal marker), S-100b protein (a neurotrophic factor and cytosolic marker of RGCs during embryonic development), and 68 kDa neurofilaments (a neuronal cytoskeletal marker) were also decreased in G18 PEE fetuses. At G14, a reduction in Pax6 cortical expression was found. Our results suggest that PEE reduces Pax6 expression in undifferentiated mammalian CNS cells. This could be one of the factors that induce RGCs and neuronal alterations at end-gestation. These alterations could be involved in the pathophysiology of neurodevelopmental disorders observed in the children affected by the fetal alcohol syndrome.

A low chronic ethanol exposure induces morphological changes in the adolescent rat brain that are not fully recovered even after a long abstinence: an immunohistochemical study.

Little is known about the morphological effects of alcoholism on the developing adolescent brain and its consequences into adulthood. We studied here the relationship between two neurotransmitter systems (the serotoninergic and nitrergic) and the astrocytic and neuronal cytoskeleton immediately and long after drinking cessation of a chronic, but low, ethanol administration. Adolescent male Wistar rats were exposed to ethanol 6.6% (v/v) in drinking water for 6 weeks and studied after ending exposure or after a 10-week recovery period drinking water. Control animals received water. Brain sections were processed by immunohistochemistry using antibodies to serotonin (5-HT); glial fibrillary acidic protein (GFAP); astroglial S-100b protein; microtubule associated protein-2 (MAP-2); 200 kDa neurofilaments (Nf-200); and neuronal nitric oxide synthase (nNOS). The mesencephalic dorsal and median raphe nucleus (DRN; MRN) and three prosencephalic areas closely related to cognitive abilities (CA1 hippocampal area, striatum and frontal cortex) were studied by digital image analysis. 5-HT immunoreactivity (-ir) decreased in the DRN and recovered after abstinence and was not changed in the MRN. In the three prosencephalic areas, astrocytes' cell area (GFAP-ir cells) increased after EtOH exposure and tended to return to normality after abstinence, while cytoplasmic astroglial S100b protein-ir, relative area of MAP-2-ir and Nf-200-ir fibers decreased, and later partially recovered. In the striatum and frontal cortex, nNOS-ir decreased only after abstinence. In conclusion, in the adolescent brain, drinking cessation can partially ameliorate the ethanol-induced morphological changes on neurons and astrocytes but cannot fully return it to the basal state.

Criterios diagnósticos del síndrome alcohólico fetal y los trastornos del espectro del alcoholismo fetal / Diagnostic criteria for fetal alcohol syndrome and fetal alcohol spectrum disorders

En nuestro medio, el alcoholismo materno-fetal es un hecho casi ignorado como importante factor en la génesis de un amplio espectro de enfermedades neuropsiquiátricas del niño, el adolescente y el adulto. Los hijos de madres alcohólicas pueden presentar desde un retraso mental profundo hasta una normalidad aparente, pasando por cuadros de epilepsia, déficit de atención con/sin hiperactividad, autismoy trastorno generalizado del desarrollo, y varios tipos de trastornos del aprendizaje. En la adolescencia pueden desarrollar varios tipos de trastornos de la personalidad y adicciones a drogas. Finalmente, en la adultez, pueden presentar diferentes tipos de psicosis y trastornos afectivos, entre otros. Un gran número de estos hijos de madres alcohólicas no logran desarrollar completamente su potencialidad mental y social como individuos plenamente libres. Con frecuencia, padecen diferentes déficit cognitivos, atencionales, mnésicos y afectivos. No raramente se ven involucrados en conductas antisociales o tienen problemas escolares y laborales. En este trabajo se revisan las clasificaciones clínicas y los criterios diagnósticos en uso sobre los trastornos que surgen de la exposición prenatal al etanol; su finalidad es llamar la atención a la comunidad médica pediátrica y neuropsiquiátrica acerca de la frecuencia creciente de estos trastornos, subdiagnosticados en nuestro país.

Criterios diagnósticos del síndrome alcohólico fetal y los trastornos del espectro del alcoholismo fetal / Diagnostic criteria for fetal alcohol syndrome and fetal alcohol spectrum disorders

En nuestro medio, el alcoholismo materno-fetal es un hecho casi ignorado como importante factor en la génesis de un amplio espectro de enfermedades neuropsiquiátricas del niño, el adolescente y el adulto. Los hijos de madres alcohólicas pueden presentar desde un retraso mental profundo hasta una normalidad aparente, pasando por cuadros de epilepsia, déficit de atención con/sin hiperactividad, autismoy trastorno generalizado del desarrollo, y varios tipos de trastornos del aprendizaje. En la adolescencia pueden desarrollar varios tipos de trastornos de la personalidad y adicciones a drogas. Finalmente, en la adultez, pueden presentar diferentes tipos de psicosis y trastornos afectivos, entre otros. Un gran número de estos hijos de madres alcohólicas no logran desarrollar completamente su potencialidad mental y social como individuos plenamente libres. Con frecuencia, padecen diferentes déficit cognitivos, atencionales, mnésicos y afectivos. No raramente se ven involucrados en conductas antisociales o tienen problemas escolares y laborales. En este trabajo se revisan las clasificaciones clínicas y los criterios diagnósticos en uso sobre los trastornos que surgen de la exposición prenatal al etanol; su finalidad es llamar la atención a la comunidad médica pediátrica y neuropsiquiátrica acerca de la frecuencia creciente de estos trastornos, subdiagnosticados en nuestro país.(AU)