Anoxia-induced hippocampal LTP is regeneratively produced by glutamate and nitric oxide from the neuro-glial-endothelial axis.

Transient anoxia causes amnesia and neuronal death. This is attributed to enhanced glutamate release and modeled as anoxia-induced long-term potentiation (aLTP). aLTP is mediated by glutamate receptors and nitric oxide (·NO) and occludes stimulation-induced LTP. We identified a signaling cascade downstream of ·NO leading to glutamate release and a glutamate-·NO loop regeneratively boosting aLTP. aLTP in entothelial ·NO synthase (eNOS)-knockout mice and blocking neuronal NOS (nNOS) activity suggested that both nNOS and eNOS contribute to aLTP. Immunostaining result showed that eNOS is predominantly expressed in vascular endothelia. Transient anoxia induced a long-lasting Ca2+ elevation in astrocytes that mirrored aLTP. Blocking astrocyte metabolism or depletion of the NMDA receptor ligand D-serine abolished eNOS-dependent aLTP, suggesting that astrocytic Ca2+ elevation stimulates D-serine release from endfeet to endothelia, thereby releasing ·NO synthesized by eNOS. Thus, the neuro-glial-endothelial axis is involved in long-term enhancement of glutamate release after transient anoxia.

CNOT7 Outcompetes Its Paralog CNOT8 for Integration into The CCR4-NOT Complex.

The CCR4-NOT deadenylase complex is a major post-transcriptional regulator of eukaryotic gene expression. CNOT7 and CNOT8 are both vertebrate homologs of the yeast CCR4-NOT catalytic subunit Caf1. They are highly similar and are sometimes considered redundant, but Cnot7 and Cnot8 knockout mice exhibit different phenotypes, implying distinct physiological functions. In this study, we reveal a non-reciprocal effect of CNOT7 on CNOT8, in which CNOT8 protein is increased in the depletion of CNOT7 without corresponding changes in mRNA levels whereas CNOT7 is not affected by the loss of CNOT8. Cnot8 mRNA may be bound by the CCR4-NOT complex, suggesting that CCR4-NOT might directly regulate CNOT8 expression. Cnot8 mRNA is relatively unstable, but Cnot7 knockdown did not stabilize Cnot8 mRNA, nor did it increase translation. CNOT8 protein was also less stable than CNOT7. CNOT7 showed greater affinity than CNOT8 for the CCR4-NOT scaffold protein CNOT1 and was able to block CNOT8 from binding to CNOT1. Depletion of CNOT7 increased CNOT8 incorporation into the CCR4-NOT complex and stabilized CNOT8. These data suggest that CNOT7 is the dominant paralog in CCR4-NOT and that CNOT7 and CNOT8 protein stability is regulated in distinct ways.

Rapid Action of Retinoic Acid on the Hypothalamic Pituitary Adrenal Axis.

Retinoic acid (RA) is the active metabolite of vitamin A but is also used as a medication, primarily for acne in which the treatment regime lasts several months. A number of studies have indicated that treatment with RA over this time period impacts the hypothalamic-pituitary-adrenal (HPA) axis and may contribute to a number of the side-effects of the drug. No studies though have investigated the short-term, early effects RA may have on the HPA axis via the transcriptional pathways activated by the RA receptor. This study investigated the action of RA over 3 days on regulatory components of the HPA axis. Several key genes involved in glucocorticoid feedback pathways in the hippocampus, hypothalamus and pituitary were unchanged after 3-days exposure to RA. Key elements though in the adrenal gland involved in corticosterone and aldosterone synthesis were altered in particular with the Cyp11b2 gene downregulated in vivo and ex vivo. The rapid, 5 h, change in Cyp11b2 expression suggested this activation may be direct. These results highlight the adrenal gland as a target of short-term action of RA and potentially a trigger component in the mechanisms by which the long-term adverse effects of RA treatment occur.

Rhythmic Diurnal Synthesis and Signaling of Retinoic Acid in the Rat Pineal Gland and Its Action to Rapidly Downregulate ERK Phosphorylation.

Vitamin A is important for the circadian timing system; deficiency disrupts daily rhythms in activity and clock gene expression, and reduces the nocturnal peak in melatonin in the pineal gland. However, it is currently unknown how these effects are mediated. Vitamin A primarily acts via the active metabolite, retinoic acid (RA), a transcriptional regulator with emerging non-genomic activities. We investigated whether RA is subject to diurnal variation in synthesis and signaling in the rat pineal gland. Its involvement in two key molecular rhythms in this gland was also examined: kinase activation and induction of Aanat, which encodes the rhythm-generating melatonin synthetic enzyme. We found diurnal changes in expression of several genes required for RA signaling, including a RA receptor and synthetic enzymes. The RA-responsive gene Cyp26a1 was found to change between day and night, suggesting diurnal changes in RA activity. This corresponded to changes in RA synthesis, suggesting rhythmic production of RA. Long-term RA treatment in vitro upregulated Aanat transcription, while short-term treatment had no effect. RA was also found to rapidly downregulate extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, suggesting a rapid non-genomic action which may be involved in driving the molecular rhythm in ERK1/2 activation in this gland. These results demonstrate that there are diurnal changes in RA synthesis and activity in the rat pineal gland which are partially under circadian control. These may be key to the effects of vitamin A on circadian rhythms, therefore providing insight into the molecular link between this nutrient and the circadian system.

No correlation was observed between vitamin D levels and disability of patients with multiple sclerosis between latitudes 18° and 30° South.

Objective: Vitamin D has taken center stage in research and treatment of multiple sclerosis (MS). The objective of the present study was to assess the serum vitamin D levels of a large population of patients with MS and controls living in a restricted tropical area. Methods: Data from 535 patients with MS and 350 control subjects were obtained from 14 cities around the Tropic of Capricorn. Results: The mean serum 25-OH vitamin D level was 26.07 ± 10.27 ng/mL for the control subjects, and 28.03 ± 12.19 ng/mL for patients with MS. No correlation was observed between vitamin D levels and the disability of patients over the disease duration. Conclusion: At least for the region around the Tropic of Capricorn, serum levels of vitamin D typically are within the range of 20 to 30 ng/mL for controls and patients with MS.

No correlation was observed between vitamin D levels and disability of patients with multiple sclerosis between latitudes 18° and 30° South / Não foi observada correlação entre os níveis séricos de vitamina D e a incapacidade em pacientes com esclerose múltipla entre as latitudes Sul 18° e 30°

ABSTRACT Objective: Vitamin D has taken center stage in research and treatment of multiple sclerosis (MS). The objective of the present study was to assess the serum vitamin D levels of a large population of patients with MS and controls living in a restricted tropical area. Methods: Data from 535 patients with MS and 350 control subjects were obtained from 14 cities around the Tropic of Capricorn. Results: The mean serum 25-OH vitamin D level was 26.07 ± 10.27 ng/mL for the control subjects, and 28.03 ± 12.19 ng/mL for patients with MS. No correlation was observed between vitamin D levels and the disability of patients over the disease duration. Conclusion: At least for the region around the Tropic of Capricorn, serum levels of vitamin D typically are within the range of 20 to 30 ng/mL for controls and patients with MS.

RESUMO Objetivo: Vitamina D assumiu um papel central na pesquisa e tratamento da esclerose múltipla (EM). O objetivo deste estudo foi avaliar os níveis séricos de vitamina D de pacientes com EM e controles que residem em uma área tropical. Métodos: Foram analisados dados de 535 pacientes com EM e 350 indivíduos controle em 14 cidades próximas ao Trópico de Capricórnio. Resultados: O valor médio da determinação de 25-OH vitamina D foi 26,07 ± 10,27 ng/mL para controles e 28,03 ± 12,19 ng/mL para pacientes com EM. Não houve correlação entre os níveis de vitamina D e o grau de incapacidade ao longo da duração da doença. Conclusão: Pelo menos na região que cerca o Trópico de Capricórnio, os níveis séricos de vitamina D estão entre valores de 20 a 30 ng/mL tanto para controles quanto para pacientes com EM.

A seasonal switch in histone deacetylase gene expression in the hypothalamus and their capacity to modulate nuclear signaling pathways.

Seasonal animals undergo changes in physiology and behavior between summer and winter conditions. These changes are in part driven by a switch in a series of hypothalamic genes under transcriptional control by hormones and, of recent interest, inflammatory factors. Crucial to the control of transcription are histone deacetylases (HDACs), generally acting to repress transcription by local histone modification. Seasonal changes in hypothalamic HDAC transcripts were investigated in photoperiod-sensitive F344 rats by altering the day-length (photoperiod). HDAC4, 6 and 9 were found to change in expression. The potential influence of HDACs on two hypothalamic signaling pathways that regulate transcription, inflammatory and nuclear receptor signaling, was investigated. For inflammatory signaling the focus was on NF-κB because of the novel finding made that its expression is seasonally regulated in the rat hypothalamus. For nuclear receptor signaling it was discovered that expression of retinoic acid receptor beta was regulated seasonally. HDAC modulation of NF-κB-induced pathways was examined in a hypothalamic neuronal cell line and primary hypothalamic tanycytes. HDAC4/5/6 inhibition altered the control of gene expression (Fos, Prkca, Prkcd and Ptp1b) by inducers of NF-κB that activate inflammation. These inhibitors also modified the action of nuclear receptor ligands thyroid hormone and retinoic acid. Thus seasonal changes in HDAC4 and 6 have the potential to epigenetically modify multiple gene regulatory pathways in the hypothalamus that could act to limit inflammatory pathways in the hypothalamus during long-day summer-like conditions.

A neuroendocrine role for chemerin in hypothalamic remodelling and photoperiodic control of energy balance.

Long-term and reversible changes in body weight are typical of seasonal animals. Thyroid hormone (TH) and retinoic acid (RA) within the tanycytes and ependymal cells of the hypothalamus have been implicated in the photoperiodic response. We investigated signalling downstream of RA and how this links to the control of body weight and food intake in photoperiodic F344 rats. Chemerin, an inflammatory chemokine, with a known role in energy metabolism, was identified as a target of RA. Gene expression of chemerin (Rarres2) and its receptors were localised within the tanycytes and ependymal cells, with higher expression under long (LD) versus short (SD) photoperiod, pointing to a physiological role. The SD to LD transition (increased food intake) was mimicked by 2 weeks of ICV infusion of chemerin into rats. Chemerin also increased expression of the cytoskeletal protein vimentin, implicating hypothalamic remodelling in this response. By contrast, acute ICV bolus injection of chemerin on a 12 h:12 h photoperiod inhibited food intake and decreased body weight with associated changes in hypothalamic neuropeptides involved in growth and feeding after 24 hr. We describe the hypothalamic ventricular zone as a key site of neuroendocrine regulation, where the inflammatory signal, chemerin, links TH and RA signaling to hypothalamic remodeling.

A Vitamin on the Mind: New Discoveries on Control of the Brain by Vitamin A.

Vitamin A is essential for many physiological processes and is particularly crucial during early life, when vitamin A deficiency increases mortality through elevated rates of infection. This deadly aspect of vitamin A deficiency masks other effects that, while not lethal, may nevertheless cause significant issues if vitamin A insufficiency reoccurs during later childhood or in the adult. One such effect is on the brain. Vitamin A is essential for several regions of the brain, and this chapter focuses on two regions: the hippocampus, needed for learning and memory, and the hypothalamus, necessary to maintain the body's internal physiological balance. Vitamin A, through its active metabolite retinoic acid, is required to support neuroplasticity in the hippocampus, and vitamin A deficiency has a dramatic effect on depressing learning and memory. The effects of vitamin A deficiency on the hypothalamus may lead to depression of appetite and growth. Much of this research has relied on animal studies, and it will be essential in the future to determine the full role of vitamin A in the human brain.

Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytes.

Thyroid hormone (TH) is essential for adult brain function and its actions include several key roles in the hypothalamus. Although TH controls gene expression via specific TH receptors of the nuclear receptor class, surprisingly few genes have been demonstrated to be directly regulated by TH in the hypothalamus, or the adult brain as a whole. This study explored the rapid induction by TH of retinaldehyde dehydrogenase 1 (Raldh1), encoding a retinoic acid (RA)-synthesizing enzyme, as a gene specifically expressed in hypothalamic tanycytes, cells that mediate a number of actions of TH in the hypothalamus. The resulting increase in RA may then regulate gene expression via the RA receptors, also of the nuclear receptor class. In vivo exposure of the rat to TH led to a significant and rapid increase in hypothalamic Raldh1 within 4 hours. That this may lead to an in vivo increase in RA is suggested by the later induction by TH of the RA-responsive gene Cyp26b1. To explore the actions of RA in the hypothalamus as a potential mediator of TH control of gene regulation, an ex vivo hypothalamic rat slice culture method was developed in which the Raldh1-expressing tanycytes were maintained. These slice cultures confirmed that TH did not act on genes regulating energy balance but could induce Raldh1. RA has the potential to upregulate expression of genes involved in growth and appetite, Ghrh and Agrp. This regulation is acutely sensitive to epigenetic changes, as has been shown for TH action in vivo. These results indicate that sequential triggering of two nuclear receptor signalling systems has the capability to mediate some of the functions of TH in the hypothalamus.

Expression of the retinoic acid catabolic enzyme CYP26B1 in the human brain to maintain signaling homeostasis.

Retinoic acid (RA) is a potent regulator of gene transcription via its activation of a set of nuclear receptors controlling transcriptional activation. Precise maintenance of where and when RA is generated is essential and achieved by local expression of synthetic and catabolic enzymes. The catabolic enzymes Cyp26a1 and Cyp26b1 have been studied in detail in the embryo, where they limit gradients of RA that form patterns of gene expression, crucial for morphogenesis. This paracrine role of RA has been assumed to occur in most tissues and that the RA synthetic enzymes release RA at a site distant from the catabolic enzymes. In contrast to the embryonic CNS, relatively little is known about RA metabolism in the adult brain. This study investigated the distribution of Cyp26a1 and Cyp26b1 transcripts in the rat brain, identifying several novel regions of expression, including the cerebral cortex for both enzymes and striatum for Cyp26b1. In vivo use of a new and potent inhibitor of the Cyp26 enzymes, ser 2-7, demonstrated a function for endogenous Cyp26 in the brain and that hippocampal RA levels can be raised by ser 2-7, altering the effect of RA on differential patterning of cell proliferation in the hippocampal region of neurogenesis, the subgranular zone. The expression of CYP26A1 and CYP26B1 was also investigated in the adult human brain and colocalization of CYP26A1 and the RA synthetic enzyme RALDH2 indicated a different, autocrine role for RA in human hippocampal neurons. Studies with the SH-SY5Y human neuroblastoma cell line implied that the co-expression of RA synthetic and catabolic enzymes maintains retinoid homeostasis within neurons. This presents a novel view of RA in human neurons as part of an autocrine, intracellular signaling system.

Patients with multiple sclerosis do not necessarily consume more alcohol or tobacco than the general population / Pacientes com esclerose múltipla não necessariamente consomem mais álcool ou tabaco do que a população geral

Purpose Recent papers suggest that patients with multiple sclerosis (MS) are prone to alcohol misuse. This may be due to the combination of a lifelong and disabling disease with a psychiatric profile typical of MS. The objective of the present study was to assess these findings in a culturally different population of patients with MS.Method The present case-control transversal study assessed 168 patients with MS and 168 control subjects from Brazil.Results There were no evidence that patients with MS drank more alcohol or, smoked more than did controls. In fact, control subjects had a significantly higher alcohol consumption. The only trait associated to higher alcohol consumption was anxiety, both for patients and controls.Conclusion Unlike previous reports in the literature, patients with MS in our study did not drink or smoked more than a control population.

Propósito Artigos recentes sugerem que pacientes com esclerose múltipla (EM) tem tendência ao abuso de álcool. Isto poderia se dever à combinação de uma doença crônica e incapacitante e um perfil psiquiátrico típico da EM. O objetivo do presente estudo foi avaliar estes achados em uma população de pacientes com EM culturalmente diferente.Método O presente estudo caso-controle transversal avaliou 168 pacientes com EM e 168 controles, todos brasileiros.Resultados Não houve evidência que pacientes com EM usassem mais álcool ou tabaco do que os controles. Na verdade, os controles apresentavam um consumo significativamente maior de álcool. O único aspecto associado ao maior consumo de álcool foi a ansiedade, tanto para pacientes quanto para controles.Conclusão Ao contrário de outros dados da literatura, pacientes com EM neste nosso estudo não bebem ou fumam mais do que a população controle.

Patients with multiple sclerosis do not necessarily consume more alcohol or tobacco than the general population.

Purpose Recent papers suggest that patients with multiple sclerosis (MS) are prone to alcohol misuse. This may be due to the combination of a lifelong and disabling disease with a psychiatric profile typical of MS. The objective of the present study was to assess these findings in a culturally different population of patients with MS.Method The present case-control transversal study assessed 168 patients with MS and 168 control subjects from Brazil.Results There were no evidence that patients with MS drank more alcohol or, smoked more than did controls. In fact, control subjects had a significantly higher alcohol consumption. The only trait associated to higher alcohol consumption was anxiety, both for patients and controls.Conclusion Unlike previous reports in the literature, patients with MS in our study did not drink or smoked more than a control population.

Expression in the human brain of retinoic acid induced 1, a protein associated with neurobehavioural disorders.

Retinoic acid induced 1 (RAI1) is a protein of uncertain mechanism of action which nevertheless has been the focus of attention because it is a major contributing factor in several human developmental disorders including Smith-Magenis and Potocki-Lupski syndromes. Further, RAI1 may be linked to adult neural disorders with developmental origins such as schizophrenia and autism. The protein has been extensively examined in the rodent but very little is known about its distribution in the human central nervous system. This study demonstrated the presence of RAI1 transcript in multiple regions of the human brain. The cellular expression of RAI1 protein in the human brain was found to be similar to that described in the mouse, with high levels in neurons, but not glia, of the dentate gyrus and cornus ammonis of the hippocampus. In the cerebellum, a second region of high expression, RAI1 was present in Purkinje cells, but not granule cells. RAI1 was also found in neurons of the occipital cortex. The expression of this retinoic acid-induced protein matched well in the hippocampus with expression of the retinoic acid receptors. The subcellular distribution of human neuronal RAI1 indicated its presence in both cytoplasm and nucleus. Overall, human RAI1 protein was found to be a highly expressed neuronal protein whose distribution matches well with its role in cognitive and motor skills.

The evidence for a beneficial role of vitamin A in multiple sclerosis.

Vitamin A is an essential nutrient with important roles in immunological responses and in brain development. Its main metabolite is retinoic acid (RA), which is responsible for the neuroimmunological functions related to vitamin A. In the brain, RA is known to have interactions with other nuclear receptor-mediated signalling pathways. RA is involved in plasticity, regeneration, cognition and behaviour. In the peripheral blood, RA plays a major role both in increasing tolerance and in decreasing inflammation, through balancing T-lymphocyte populations. It is likely that RA synthesis may be manipulated by complex cross-talk among cells during infection and inflammation. The role of vitamin A in multiple sclerosis (MS) could be dual: at the same time as it decreases inflammation and increases tolerance of autoimmunity, it may also help in brain protection. The present review discusses the beneficial effects that vitamin A might have for controlling MS, although it must be clearly stated that, at the present time, there is no clear indication for using vitamin A as a treatment for MS. However, the results from the present review should encourage clinical trials with vitamin supplementation as a potential treatment or as an add-on option. Vitamin A acts in synergy with vitamin D, and the immunological homeostasis ensured by these vitamins should not be unbalanced in favour of only one of them.

The rhythm of retinoids in the brain.

The retinoids are a family of compounds that in nature are derived from vitamin A or pro-vitamin A carotenoids. An essential part of the diet for mammals, vitamin A has long been known to be essential for many organ systems in the adult. More recently, however, they have been shown to be necessary for function of the brain and new discoveries point to a central role in processes ranging from neuroplasticity to neurogenesis. Acting in several regions of the central nervous system including the eye, hippocampus and hypothalamus, one common factor in its action is control of biological rhythms. This review summarizes the role of vitamin A in the brain; its action through the metabolite retinoic acid via specific nuclear receptors, and the regulation of its concentration through controlled synthesis and catabolism. The action of retinoic acid to regulate several rhythms in the brain and body, from circadian to seasonal, is then discussed to finish with the importance of retinoic acid in the regular pattern of sleep. We review the role of vitamin A and retinoic acid (RA) as mediators of rhythm in the brain. In the suprachiasmatic nucleus and hippocampus they control expression of circadian clock genes while in the cortex retinoic acid is required for delta oscillations of sleep. Retinoic acid is also central to a second rhythm that keeps pace with the seasons, regulating function in the hypothalamus and pineal gland.

Fenretinide treatment prevents diet-induced obesity in association with major alterations in retinoid homeostatic gene expression in adipose, liver, and hypothalamus.

The synthetic retinoid, Fenretinide (FEN), inhibits obesity and insulin resistance in mice and is in early clinical trials for treatment of insulin resistance in obese humans. We aimed to determine whether alterations in retinoic acid (RA)-responsive genes contribute to the beneficial effects of FEN. We examined the effect of FEN on 3T3-L1 adipocyte differentiation and alterations in gene expression in C57Bl/6 and retinaldehyde dehydrogenase (RALDH) 1 knockout (KO) mice fed a high-fat (HF) diet. FEN completely inhibited adipocyte differentiation by blocking CCAAT/enhancer-binding protein (C/EBP) α/peroxisome proliferator-activated receptor (PPAR) γ-mediated induction of downstream genes and upregulating RA-responsive genes like cellular retinol-binding protein-1. In mice fed an HF diet, RA-responsive genes were markedly increased in adipose, liver, and hypothalamus, with short-term and long-term FEN treatment. In adipose, FEN inhibited the downregulation of PPARγ and improved insulin sensitivity and the levels of adiponectin, resistin, and serum RBP (RBP4). FEN inhibited hyperleptinemia in vivo and leptin expression in adipocytes. Surprisingly, hypothalamic neuropeptide Y expression was completely suppressed, suggesting a central effect of FEN to normalize hyperglycemia. Moreover, FEN induced RA-responsive genes in RALDH1 KO mice, demonstrating that FEN can augment RA signaling when RA synthesis is impaired. We show that FEN-mediated beneficial effects are through alterations in retinoid homeostasis genes, and these are strong candidates as therapeutic targets for the treatment of obesity and insulin resistance.

A vitamin for the brain.

In the central nervous system (CNS) the function of retinoic acid, the active metabolite of vitamin A, is best understood from its action in guiding embryonic development; as development comes to completion, retinoic acid signaling declines. However, it is increasingly recognized that this signaling mechanism does not disappear in the adult brain but becomes more regionally focused and takes on new roles. These functions are often tied to processes of neural plasticity whether in the hippocampus, through homeostatic neural plasticity, the olfactory bulb or the hypothalamus. The role of retinoic acid in the control of plastic processes has led to suggestions of its involvement in neural disorders, both degenerative and psychiatric. This review presents a snapshot of developments in these areas over recent years.

Photoperiodic expression of two RALDH enzymes and the regulation of cell proliferation by retinoic acid in the rat hypothalamus.

Retinoic acid (RA) has been found to regulate hypothalamic function, but precisely where it acts is unknown. This study shows expression of retinaldehyde dehydrogenase (RALDH) enzymes in tanycytes that line the third ventricle in an area overlapping with the site of hypothalamic neural stem cells. The influence of RA was examined on the proliferation of progenitors lining the third ventricle using organotypic slice cultures. As has been shown in other regions of neurogenesis, RA was found to inhibit proliferation. Investigations of the dynamics of RALDH1 expression in the rat hypothalamus have shown that this enzyme is in tanycytes under photoperiodic control with highest levels during long versus short days. In parallel to this shift in RA synthesis, cell proliferation in the third ventricle was found to be lowest during long days when RA was highest, implying that RALDH1 synthesized RA may regulate neural stem cell proliferation. A second RA synthesizing enzyme, RALDH2 was also present in tanycytes lining the third ventricle. In contrast to RALDH1, RALDH2 showed little change with photoperiodicity, but surprisingly the protein was present in the apparent absence of mRNA transcript and it is hypothesized that the endocytic tanycytes may take this enzyme up from the cerebrospinal fluid (CSF).

Synaptic Ras GTPase activating protein regulates pattern formation in the trigeminal system of mice.

The development of ordered connections or "maps" within the nervous system is a common feature of sensory systems and is crucial for their normal function. NMDA receptors are known to play a key role in the formation of these maps; however, the intracellular signaling pathways that mediate the effects of glutamate are poorly understood. Here, we demonstrate that SynGAP, a synaptic Ras GTPase activating protein, is essential for the anatomical development of whisker-related patterns in the developing somatosensory pathways in rodent forebrain. Mice lacking SynGAP show only partial segregation of barreloids in the thalamus, and thalamocortical axons segregate into rows but do not form whisker-related patches. In cortex, layer 4 cells do not aggregate to form barrels. In Syngap(+/-) animals, barreloids develop normally, and thalamocortical afferents segregate in layer 4, but cell segregation is retarded. SynGAP is not necessary for the development of whisker-related patterns in the brainstem. Immunoelectron microscopy for SynGAP from layer 4 revealed a postsynaptic localization with labeling in developing postsynaptic densities (PSDs). Biochemically, SynGAP associates with the PSD in a PSD-95-independent manner, and Psd-95(-/-) animals develop normal barrels. These data demonstrate an essential role for SynGAP signaling in the activity-dependent development of whisker-related maps selectively in forebrain structures indicating that the intracellular pathways by which NMDA receptor activation mediates map formation differ between brain regions and developmental stage.