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S L McIntire

Publications and source records attributed to S L McIntire.

9 recordsLinked to original sources

State-dependency in C. elegans.

Memory and the expression of learned behaviors by an organism are often triggered by contextual cues that resemble those that were present when the initial learning occurred. In state-dependent learning, the cue eliciting a learned behavior is a neuroactive drug; behaviors initially learned during exposure to centrally acting compounds such as ethanol are subsequently recalled better if the drug stimulus is again present during testing. Although state-dependent learning is well documented in many vertebrate systems, the molecular mechanisms underlying state-dependent learning and other forms of contextual learning are not understood. Here we demonstrate and present a genetic analysis of state- dependent adaptation in Caenorhabditis elegans. C. elegans normally exhibits adaptation, or reduced behavioral response, to an olfactory stimulus after prior exposure to the stimulus. If the adaptation to the olfactory stimulus is acquired during ethanol administration, the adaptation is subsequently displayed only if the ethanol stimulus is again present. cat-1 and cat-2 mutant animals are defective in dopaminergic neuron signaling and are impaired in state dependency, indicating that dopamine functions in state-dependent adaptation in C. elegans.

Adaptation, Physiological↗

A family of yeast proteins mediating bidirectional vacuolar amino acid transport.

Seven genes in Saccharomyces cerevisiae are predicted to code for membrane-spanning proteins (designated AVT1-7) that are related to the neuronal gamma-aminobutyric acid-glycine vesicular transporters. We have now demonstrated that four of these proteins mediate amino acid transport in vacuoles. One protein, AVT1, is required for the vacuolar uptake of large neutral amino acids including tyrosine, glutamine, asparagine, isoleucine, and leucine. Three proteins, AVT3, AVT4, and AVT6, are involved in amino acid efflux from the vacuole and, as such, are the first to be shown directly to transport compounds from the lumen of an acidic intracellular organelle. This function is consistent with the role of the vacuole in protein degradation, whereby accumulated amino acids are exported to the cytosol. Protein AVT6 is responsible for the efflux of aspartate and glutamate, an activity that would account for their exclusion from vacuoles in vivo. Transport by AVT1 and AVT6 requires ATP for function and is abolished in the presence of nigericin, indicating that the same pH gradient can drive amino acid transport in opposing directions. Efflux of tyrosine and other large neutral amino acids by the two closely related proteins, AVT3 and AVT4, is similar in terms of substrate specificity to transport system h described in mammalian lysosomes and melanosomes. These findings suggest that yeast AVT transporter function has been conserved to control amino acid flux in vacuolar-like organelles.

Amino Acid Sequence↗

Identification and characterization of the vesicular GABA transporter.

Synaptic transmission involves the regulated exocytosis of vesicles filled with neurotransmitter. Classical transmitters are synthesized in the cytoplasm, and so must be transported into synaptic vesicles. Although the vesicular transporters for monoamines and acetylcholine have been identified, the proteins responsible for packaging the primary inhibitory and excitatory transmitters, gamma-aminobutyric acid (GABA) and glutamate remain unknown. Studies in the nematode Caenorhabditis elegans have implicated the gene unc-47 in the release of GABA. Here we show that the sequence of unc-47 predicts a protein with ten transmembrane domains, that the gene is expressed by GABA neurons, and that the protein colocalizes with synaptic vesicles. Further, a rat homologue of unc-47 is expressed by central GABA neurons and confers vesicular GABA transport in transfected cells with kinetics and substrate specificity similar to those previously reported for synaptic vesicles from the brain. Comparison of this vesicular GABA transporter (VGAT) with a vesicular transporter for monoamines shows that there are differences in the bioenergetic dependence of transport, and these presumably account for the differences in structure. Thus VGAT is the first of a new family of neurotransmitter transporters.

Amino Acid Sequence↗

Genes required for GABA function in Caenorhabditis elegans.

gamma-Aminobutyric acid (GABA) neurotransmission is widespread in vertebrate and invertebrate nervous systems. Here we use a genetic approach to identify molecules specific to GABA function. On the basis of the known in vivo roles of GABAergic neurons in controlling behaviour of the nematode Caenorhabditis elegans, we identified mutants defective in GABA-mediated behaviours. Five genes are necessary either for GABAergic neuronal differentiation or for pre- or postsynaptic GABAergic function. The gene unc-30 is required for the differentiation of a specific type of GABAergic neuron, the type-D inhibitory motor neuron. The gene unc-25 is necessary for GABA expression and probably encodes the GABA biosynthetic enzyme glutamic acid decarboxylase. The genes unc-46 and unc-47 seem to be required for normal GABA release. Finally, the gene unc-49 is apparently necessary postsynaptically for the inhibitory effect of GABA on the body muscles and might encode a protein needed for the function of a GABAA-like receptor. Some of these genes are likely to encode previously unidentified proteins required for GABA function.

Animals↗

The GABAergic nervous system of Caenorhabditis elegans.

gamma-Aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter in vertebrates and invertebrates. GABA receptors are the target of anxiolytic, antiepileptic and antispasmodic drugs, as well as of commonly used insecticides. How does a specific neurotransmitter such as GABA control animal behaviour? To answer this question, we identified all neurons that react with antisera raised against the neurotransmitter GABA in the nervous system of the nematode Caenorhabditis elegans. We determined the in vivo functions of 25 of the 26 GABAergic neurons by killing these cells with a laser microbeam in living animals and by characterizing a mutant defective in GABA expression. On the basis of the ultrastructurally defined connectivity of the C. elegans nervous system, we deduced how these GABAergic neurons act to control the body and enteric muscles necessary for different behaviours. Our findings provide evidence that GABA functions as an excitatory as well as an inhibitory neurotransmitter.

Animals↗

Genes necessary for directed axonal elongation or fasciculation in C. elegans.

The outgrowth of single axons through different cellular environments requires distinct sets of genes in the nematode C. elegans. Three genes are required for the pioneering circumferential outgrowth of identified motor neuron axons between the lateral hypodermal cell membrane and the basal lamina. Three other genes are required for the longitudinal outgrowth of these axons along preexisting axon bundles as well as for the fasciculation of axons within these neuron bundles. Five additional genes are required for circumferential outgrowth, longitudinal outgrowth, and fasciculation; mutations in three of these genes disrupt axon ultrastructure, suggesting that they function in axon formation rather than in axon guidance.

Animals↗

A genetic pathway for the development of the Caenorhabditis elegans HSN motor neurons.

Thirty-five genes define a pathway for the development of the hermaphrodite-specific neurons (HSNs) in Caenorhabditis elegans. Some of these genes affect only one HSN trait, demonstrating that HSN migration, axonal outgrowth and serotonin expression are mutually independent events in HSN development; others, some of which are regulatory, affect multiple HSN traits. Nearly all are pleiotropic, revealing that the genes specifying HSN development also function in the development of other cell types.

Animals↗

Nicotinic-catecholaminergic interactions in rat brain: evidence for cholinergic nicotinic and muscarinic interactions with hypothalamic epinephrine.

The i.p. injection of nicotine produced several changes in regional catecholamine concentrations in rat brain. These changes were blocked by the centrally active nicotinic antagonist mecamylamine, but not by the quaternary nicotinic antagonist hexamethonium. An examination of the effects of various cholinergic agents on hypothalamic epinephrine concentrations revealed several interesting findings. Central muscarinic antagonism or peripheral muscarinic agonism decreased hypothalamic epinephrine concentrations. The anticholinesterase physostigmine decreased hypothalamic epinephrine concentrations and this effect was blocked by the centrally acting nicotinic antagonist mecamylamine, but not by hexamethonium, scopolamine or methscopolamine. These findings indicate an interaction of cholinergic receptors, both nicotinic and muscarinic, with hypothalamic epinephrine.

Animals↗