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David A Carter

Publications and source records attributed to David A Carter.

11 recordsLinked to original sources
PubMed2006

Nucleus-specific abnormalities of GABAergic synaptic transmission in a genetic model of absence seizures.

Human and experimental studies indicate that molecular genetic changes in GABA(A) receptors may underlie the expression of spike-and-waves discharges (SWDs) occurring during absence seizures. However, the full spectrum of the genetic defects underlying these seizures has only been partially elucidated, the expression and functional profiles of putative abnormal protein(s) within the thalamocortical network are undefined, and the pathophysiological mechanism(s) by which these proteins would lead to absence paroxysms are poorly understood. Here we investigated GABA(A) inhibitory postsynaptic currents (IPSCs) in key thalamocortical areas, i.e., the somatosensory cortex, ventrobasal thalamus (VB) and nucleus reticularis thalami (NRT), in preseizure genetic absence epilepsy rats from Strasbourg (GAERS), a well-established genetic model of typical absence seizures that shows no additional neurological abnormalities, and compared their properties to age-matched non-epileptic controls (NECs). Miniature GABA(A) IPSCs of VB and cortical layers II/III neurons were similar in GAERS and NEC, whereas in GAERS NRT neurons they had 25% larger amplitude, 40% faster decay. In addition, baclofen was significantly less effective in decreasing the frequency of NRT mIPSCs in GAERS than in NEC, whereas no difference was observed for cortical and VB mIPSCS between the two strains. Paired-pulse depression was 45% smaller in GAERS NRT, but not in VB, and was insensitive to GABA(B) antagonists. These results point to subtle, nucleus-specific, GABA(A) receptor abnormalities underlying SWDs of typical absence seizures rather than a full block of these receptors across the whole thalamocortical network, and their occurrence prior to seizure onset suggests that they might be of epileptogenic significance.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2005

A novel pineal-specific product of the oligopeptide transporter PepT1 gene: circadian expression mediated by cAMP activation of an intronic promoter.

The oligopeptide transporter 1, PepT1, is a member of the Slc15 family of 12 membrane-spanning domain transporters; PepT1 has proton/peptide cotransport activity and is selectively expressed in intestinal epithelial cells, where it is responsible for the nutritional absorption of di- and tri-peptides. Here, a novel PepT1 gene product has been identified in the rat pineal gland, termed pgPepT1. It encodes a 150-amino acid protein encompassing the C-terminal 3 membrane-spanning domains of intestinal PepT1 protein, with 3 additional N-terminal residues. Expression of pgPepT1 appears to be restricted to the pineal gland and follows a marked circadian pattern with >100-fold higher levels of mRNA occurring at night; this is accompanied by an accumulation of membrane-associated pgPepT1 protein ( approximately 16 kDa). The daily rhythm in pgPepT1 mRNA is regulated by the well described neural pathway that controls pineal melatonin production. This includes the retina, the circadian clock in the suprachiasmatic nucleus, central structures, and projections from the superior cervical ganglia; activation of this pathway results in the release of norepinephrine. Here it was found that pgPepT1 expression is mediated by a norepinephrine-->cyclic AMP mechanism that activates an alternative promoter located in intron 20 of the gene. pgPepT1 protein was found to have transporter-modulator activity; it could contribute to circadian changes in pineal function through this mechanism.

Amino Acid Sequence↗
PubMed2005

Identification of two further splice variants of GABABR1 characterizes the conserved micro-exon 4 as a hot spot for regulated splicing in the rat brain.

Inhibitory neurotransmission in the mammalian brain is principally mediated by gamma-aminobutyric acid (GABA) acting through different subtypes of cell membrane GABA receptor (GABAR). The expression of one GABAR gene, GABABR1, is distinguished by the expression of multiple splice variants that encode different isoforms of the receptor. In the present study, we have identified two novel GABABR1 variants, GABABR1h (R1h) and GABABR1i (R1i), which appear to arise from alternative splicing of the GABABR1 gene. The expression of R1h and R1i is differentially regulated in brain and peripheral tissues, but expression is not altered in the brain of a genetic model of absence epilepsy (GAERS rat [genetic absence epilepsy rat from Strasbourg]). Both the R1h and R1i variants exhibit a novel 80-bp insert downstream of exon 4 that is flanked by consensus splice sites, and both encode C-terminal-truncated proteins. The new insight into the family of GABABR1 variants gained from this study identifies exon 4 as a preferred locus, or hot spot for regulated splicing in the GABABR1 gene. This finding correlates with the micro-exonic nature of exon 4 (21 bp). Bioinformatic analysis of micro-exon 4 and its flanking pre-mRNA sequences has revealed multiple, potentially competitive, exonic splicing enhancers that provide a mechanistic basis for the preponderance of alternative splicing events at this locus. Conservation of GABABR1 micro-exon 4 across species suggests a conserved functional role, facilitating either N-terminal protein production or post-transcriptional gene regulation through regulated splicing coupled to transcript decay.

Alternative Splicing↗
PubMed2004

Mitogen-activated protein kinase phosphatase-1 (MKP-1): >100-fold nocturnal and norepinephrine-induced changes in the rat pineal gland.

The norepinephrine-driven increase in mitogen-activated protein kinase (MAPK) activity is part of the mechanism that regulates arylalkylamine N-acetyltransferase (AA-NAT) activity in the rat pineal gland. We now report a marked nocturnal increase in the expression of a MAPK phosphatase, MAP kinase phosphatase-1 (MKP-1), that was blocked by maintaining animals in constant light or treatment with propranolol. MKP-1 expression was regulated by norepinephrine acting through both alpha- and beta-adrenergic receptors. These results establish a nocturnal increase in pineal MKP-1 expression that is under the control of a photoneural system. Because substrates of MKP-1 can influence AA-NAT activity, our findings suggest the involvement of MKP-1 in the regulation of the nocturnal AA-NAT signal.

Acetyltransferases↗
PubMed2004

Circadian dependency of nocturnal immediate-early protein induction in rat retina.

Daily rhythms in the mammalian retina are regulated by an endogenous circadian clock. Previously it was found that neuronal elements of the rat retina respond to light:dark (L:D) transitions with cell-specific changes in expression of the c-fos gene. Using a pan-Fos antibody to probe Western blots of rat retina, we have now shown that darkness is associated with a 60-fold increase in c-Fos protein, whereas levels of FosB and Fos-related antigens are invariant. The induction of c-Fos exhibits circadian dependency; accumulation of c-Fos protein was significantly enhanced, by a factor of 2.5-fold, when darkness onset was coincident with the established L:D transition. c-Fos exhibited only a low amplitude circadian rhythm in the absence of L:D cycles. Similar results were obtained for another immediate early gene (IEG) protein, Egr-1. These findings show that IEG induction in the rodent retina exhibits circadian clock dependency.

Animals↗
PubMed2004

Comprehensive strategies to study neuronal function in transgenic animal models.

In the last 20 years of transgenic research, transgenic technology has been developed and refined to provide a seemingly comprehensive range of experimental approaches to questions of neuronal gene function; however, parallel developments in other technologies, such as whole genome sequencing and microarray analysis of gene expression, has meant that the questions have gotten harder. The complexity of neuronal systems and the difficulty of modeling neurologic diseases in rodents also present considerable challenges to molecular neuroscientists. Future functional genomic studies of brain and behavior will involve the full range of available transgenic methods and the incorporation of new technologies, including RNA interference.

Animals↗
PubMed2004

Photic stimulation inhibits growth hormone secretion in rats: a hypothalamic mechanism for transient entrainment.

It is well established that photic cues are used by the suprachiasmatic nucleus (SCN) to entrain circadian rhythms to the light/dark cycle, but the role of photic stimuli in the regulation of ultradian neuroendocrine rhythms is ill defined. In relation to the rhythms of GH secretion, recent studies have shown that nocturnal photic stimulation induces gene expression not only in the SCN but also in periventricular (PeN) somatostatin (SRIF) neurons. We have, therefore, investigated the effect of nocturnal photic stimulation on spontaneous and induced GH secretion in conscious rats. Nocturnal photic stimulation (lights on at 2400 h for 1 h) suppressed spontaneous GH secretion in male and female rats and reduced the GH response to SRIF withdrawal and iv injection of GH-releasing factor. A similar trough in GH secretion was also observed during the first hour of the normal light phase (0600 h). Using immunohistochemical analysis, we have also shown that expression of the transcription factor, Egr-1, is induced at the commencement of the light phase in the SCN, PeN, and medial preoptic nucleus. This effect is abolished by maintaining rats in the dark during this period. These data, together with our previous demonstration that 50% of SRIF-positive neurons in the PeN coexpress Egr-1 after photic stimulation, suggest that activation of SRIF neurons in the PeN may entrain the episodes of GH secretion to the dark/light interface. However, the absence of synchrony in GH pulses between animals by the second half of the light period suggests that this entrainment is transient.

Animals↗
PubMed2004

NGFI-B (Nurr77/Nr4a1) orphan nuclear receptor in rat pinealocytes: circadian expression involves an adrenergic-cyclic AMP mechanism.

NGFI-B (Nur77/Nr4a1) is a member of a nuclear steroid receptor subgroup that includes the related factors Nurr1 (Nr4a2) and NOR-1 (Nr4a3). These proteins do not have recognized ligands and in fact function independently as orphan receptors with transcriptional regulatory activity. In the present study, expression of the NGFI-B gene in the rat pineal gland was found to exhibit a robust circadian rhythm, with elevated levels of NGFI-B mRNA occurring at night. The rhythm of NGFI-B mRNA is translated into a circadian rhythm of NGFI-B protein, which accumulates in the nucleus of pinealocytes. In addition, there is a parallel marked nocturnal increase in pineal DNA binding activity to a NGFI-B response element (NBRE, AAAGGTCA). Pharmacological studies indicate that NGFI-B mRNA and protein levels are elevated via activation of adrenergic receptors. NGFI-B protein levels are also elevated by dibutyryl cyclic AMP, as in other systems. In the pineal gland, regulation of NGFI-B expression also involves the AP-1 protein Fra-2, based on studies with a transgenic Fra-2 knockdown rat, in which pineal NGFI-B expression increases. This set of observations extends the number of pineal genes that are known to be regulated by Fra-2, and also provides the first indication that a member of the NGFI-B group of nuclear receptors is involved in controlling gene expression in the pineal gland.

Animals↗
PubMed2003

Primary central nervous system cytotoxic/suppressor T-cell lymphoma: report of a unique case and review of the literature.

Peripheral T-cell lymphoma primary to the central nervous system is a rare occurrence. The authors report a case of an 89-year-old woman who presented with a 3-month history of worsening confusion and recent onset of headache, nausea and vomiting, and upper limb tremors. Computed tomography and magnetic resonance imaging examinations demonstrated a 4.5-cm solitary brain mass in the right basal ganglia with compression along the ventricular system. No other lesion was found in the patient. Histologic and immunohistochemical studies of a stereotactic biopsy of the mass showed a T-cell lymphoproliferative lesion positive for CD3, CD8, CD57, and T-cell intracellular antigen 1 and negative for CD4, CD56, CD30, anaplastic lymphoma kinase, and CD20. A monoclonal T-cell receptor-gamma gene rearrangement was detected by polymerase chain reaction analysis of genomic DNA isolated from paraffin-embedded tumor tissue sections. These findings were consistent with peripheral T-cell lymphoma of cytotoxic/suppressor phenotype, resembling the phenotype of T-cell large granular cell leukemia. To the authors' best knowledge, this represents the first reported case of primary brain T-cell lymphoma with a cytotoxic/suppressor immunophenotype. A brief review of the literature of primary brain T-cell lymphoma is also presented.

Aged↗
PubMedDate not supplied

Id-1 expression defines a subset of vimentin/S-100beta-positive, GFAP-negative astrocytes in the adult rat pineal gland.

Id proteins are dominant negative members of the helix-loop-helix (HLH) transcription factor family which are involved in the differentation of many cell types, including glia. We have recently identified the adult rat pineal gland as a major site of Id-1 and Id-3 expression. In the present study, double fluorescence immunocytochemical analysis was used to examine the co-localization of Id-1 and Id-3 with both neuronal (synaptophysin, betaIII-tubulin) and astrocytic markers (GFAP, vimentin, S-100beta) in the rat pineal. In addition to localizing Id-1 and Id-3 protein to the melatonin-producing pinealocytes, we have also made the novel observation that Id-1, but not Id-3, is highly expressed in a population of vimentin-positive/S-100beta-positive/GFAP-negative astrocytes. Surprisingly, Id-1 was primarily cytoplasmic in these cells, and expression extended throughout the cellular processes. The pineal has been recognized previously as a unique region of the central nervous system in which a vimentin-positive/GFAP-negative glial phenotype is maintained in adult mammals. The exclusion of Id-1 from GFAP-positive cells, and expression in a population of vimentin-positive pineal astrocytes is evidence of a role for Id-1 in the adult stabilization of one form of astrocyte. These results identify the rat pineal gland as a model system for the functional analysis of Id-1.

Animals↗