Jon Storm-Mathisen - Academia.edu (original) (raw)

Papers by Jon Storm-Mathisen

The Journal of Neuroscience, 2000

Protein phosphatase inhibitor-1 (I-1) has been proposed as a regulatory element in the signal tra... more Protein phosphatase inhibitor-1 (I-1) has been proposed as a regulatory element in the signal transduction cascade that couples postsynaptic calcium influx to long-term changes in synaptic strength. We have evaluated this model using mice lacking I-1. Recordings made in slices prepared from mutant animals and also in anesthetized mutant animals indicated that long-term potentiation (LTP) is deficient at perforant path-dentate granule cell synapses. In vitro, this deficit was restricted to synapses of the lateral perforant path. LTP at Schaffer collateral-CA1 pyramidal cell synapses remained normal. Thus, protein phosphatase-1-mediated regulation of NMDA receptordependent synaptic plasticity involves heterogeneous molecular mechanisms, in both different dendritic subregions and different neuronal subtypes. Examination of the performance of I-1 mutants in spatial learning tests indicated that intact LTP at lateral perforant path-granule cell synapses is either redundant or is not involved in this form of learning.

The Journal of Neuroscience, 1995

The Journal of Neuroscience, 1998

A transporter thought to mediate accumulation of GABA into synaptic vesicles has recently been cl... more A transporter thought to mediate accumulation of GABA into synaptic vesicles has recently been cloned (McIntire et al., 1997). This vesicular GABA transporter (VGAT), the first vesicular amino acid transporter to be molecularly identified, differs in structure from previously cloned vesicular neurotransmitter transporters and defines a novel gene family. Here we use antibodies specific for N-and C-terminal epitopes of VGAT to localize the protein in the rat CNS. VGAT is highly concentrated in the nerve endings of GABAergic neurons in the brain and spinal cord but also in glycinergic nerve endings. In contrast, hippocampal mossy fiber boutons, which although glutamatergic are known to contain GABA, lack VGAT immunoreactivity. Post-embedding immunogold quantification shows that the protein specifically associates with synaptic vesicles. Triple labeling for VGAT, GABA, and glycine in the lateral oliva superior revealed a higher expression of VGAT in nerve endings rich in GABA, with or without glycine, than in others rich in glycine only. Although the great majority of nerve terminals containing GABA or glycine are immunopositive for VGAT, subpopulations of nerve endings rich in GABA or glycine appear to lack the protein. Additional vesicular transporters or alternative modes of release may therefore contribute to the inhibitory neurotransmission mediated by these two amino acids.

Biochemical Society Transactions, 1987

Physiological Reviews, 2015

Neuroglia, the “glue” that fills the space between neurons in the central nervous system, takes a... more Neuroglia, the “glue” that fills the space between neurons in the central nervous system, takes active part in nerve cell signaling. Neuroglial cells, astroglia, oligodendroglia, and microglia, are together about as numerous as neurons in the brain as a whole, and in the cerebral cortex grey matter, but the proportion varies widely among brain regions. Glial volume, however, is less than one-fifth of the tissue volume in grey matter. When stimulated by neurons or other cells, neuroglial cells release gliotransmitters by exocytosis, similar to neurotransmitter release from nerve endings, or by carrier-mediated transport or channel flux through the plasma membrane. Gliotransmitters include the common neurotransmitters glutamate and GABA, the nonstandard amino acid d-serine, the high-energy phosphate ATP, and l-lactate. The latter molecule is a “buffer” between glycolytic and oxidative metabolism as well as a signaling substance recently shown to act on specific lactate receptors in th...

Proceedings of the National Academy of Sciences of the United States of America, Jan 22, 2001

Neuronal synchronization in the olfactory bulb has been proposed to arise from a diffuse action o... more Neuronal synchronization in the olfactory bulb has been proposed to arise from a diffuse action of glutamate released from mitral cells (MC, olfactory bulb relay neurons). According to this hypothesis, glutamate spills over from dendrodendritic synapses formed between MC and granule cells (GC, olfactory bulb interneurons) to activate neighboring MC. The excitation of MC is balanced by a strong inhibition from GC. Here we show that MC excitation is caused by glutamate released from bulbar interneurons located in the GC layer. These reciprocal synapses depend on an unusual, 2-amino-5-phosphonovaleric acid-resistant, N-methyl-d-aspartate receptor. This type of feedback excitation onto relay neurons may strengthen the original sensory input signal and further extend the function of the dendritic microcircuit within the main olfactory bulb.

PLoS ONE, 2011

In the brain, glutamate is an extracellular transmitter that mediates cell-to-cell communication.... more In the brain, glutamate is an extracellular transmitter that mediates cell-to-cell communication. Prior to synaptic release it is pumped into vesicles by vesicular glutamate transporters (VGLUTs). To inactivate glutamate receptor responses after release, glutamate is taken up into glial cells or neurons by excitatory amino acid transporters (EAATs). In the pancreatic islets of Langerhans, glutamate is proposed to act as an intracellular messenger, regulating insulin secretion from b-cells, but the mechanisms involved are unknown. By immunogold cytochemistry we show that insulin containing secretory granules express VGLUT3. Despite the fact that they have a VGLUT, the levels of glutamate in these granules are low, indicating the presence of a protein that can transport glutamate out of the granules. Surprisingly, in b-cells the glutamate transporter EAAT2 is located, not in the plasma membrane as it is in brain cells, but exclusively in insulin-containing secretory granules, together with VGLUT3. In EAAT2 knock out mice, the content of glutamate in secretory granules is higher than in wild type mice. These data imply a glutamate cycle in which glutamate is carried into the granules by VGLUT3 and carried out by EAAT2. Perturbing this cycle by knocking down EAAT2 expression with a small interfering RNA, or by over-expressing EAAT2 or a VGLUT in insulin granules, significantly reduced the rate of granule exocytosis. Simulations of granule energetics suggest that VGLUT3 and EAAT2 may regulate the pH and membrane potential of the granules and thereby regulate insulin secretion. These data suggest that insulin secretion from b-cells is modulated by the flux of glutamate through the secretory granules.

Brain Structure and Function, 2014

In mesial temporal lobe epilepsy (MTLE), spontaneous seizures likely originate from a multi-struc... more In mesial temporal lobe epilepsy (MTLE), spontaneous seizures likely originate from a multi-structural epileptogenic zone, including several regions of the limbic system connected to the hippocampal formation. In this study, we investigate the structural connectivity between the supramammillary nucleus (SuM) and the dentate gyrus (DG) in the model of MTLE induced by pilocarpine in the rat. This hypothalamic nucleus, which provides major extracortical projections to the hippocampal formation, plays a key role in the regulation of several hippocampus-dependent activities, including theta rhythms, memory function and emotional behavior, such as stress and anxiety, functions that are known to be altered in MTLE. Our findings demonstrate a marked reorganization of DG afferents originating from the SuM in pilocarpinetreated rats. This reorganization, which starts during the latent period, is massive when animals become epileptic and continue to evolve during epilepsy. It is characterized by an aberrant distribution and an increased number of axon terminals from neurons of both lateral and medial regions of the SuM, invading the entire inner molecular layer of the DG. This reorganization, which reflects an axon terminal sprouting from SuM neurons, could contribute to trigger spontaneous seizures within an altered hippocampal intrinsic circuitry. Keywords Hippocampus Á Dentate gyrus Á GAD Á VGAT Á VGLUT2 Á Hypothalamus Á SuM Rabia Soussi and Jean-Luc Boulland have contributed equally to this work.

Journal of Neuroscience, 2004

Recent studies implicate dendritic endocannabinoid release from subsynaptic dendrites and subsequ... more Recent studies implicate dendritic endocannabinoid release from subsynaptic dendrites and subsequent inhibition of neurotransmitter release from nerve terminals as a means of retrograde signaling in multiple brain regions. Here we show that type 1 cannabinoid receptor-mediated endocannabinoid signaling is not involved in the retrograde control of synaptic efficacy at inhibitory synapses between fast-spiking interneurons and pyramidal cells in layer 2/3 of the neocortex. Vesicular neurotransmitter transporters, such as vesicular glutamate transporters (VGLUTs) 1 and 2, are localized to presynaptic terminals and accumulate neurotransmitters into synaptic vesicles. A third subtype of VGLUTs (VGLUT3) was recently identified and found localized to dendrites of various cell types. We demonstrate, using multiple immunofluorescence labeling and confocal laserscanning microscopy, that VGLUT3-like immunoreactivity is present in dendrites of layer 2/3 pyramidal neurons in the rat neocortex. Electron microscopy analysis confirmed that VGLUT3-like labeling is localized to vesicular structures, which show a tendency to accumulate in close proximity to postsynaptic specializations in dendritic shafts of pyramidal cells. Dual whole-cell recordings revealed that retrograde signaling between fast-spiking interneurons and pyramidal cells was enhanced under conditions of maximal efficacy of VGLUT3-mediated glutamate uptake, whereas it was reduced when glutamate uptake was inhibited by incrementing concentrations of the nonselective VGLUT inhibitor Evans blue (0.5-5.0 M) or intracellular Cl Ϫ concentrations (4-145 mM). Our results present further evidence that dendritic vesicular glutamate release, controlled by novel VGLUT isoforms, provides fast negative feedback at inhibitory neocortical synapses, and demonstrate that glutamate can act as a retrograde messenger in the CNS.

The EMBO Journal, 2001

The system N transporter SN1 has been proposed to mediate the ef¯ux of glutamine from cells requi... more The system N transporter SN1 has been proposed to mediate the ef¯ux of glutamine from cells required to sustain the urea cycle and the glutamine±glutamate cycle that regenerates glutamate and g-aminobutyric acid (GABA) for synaptic release. We now show that SN1 also mediates an ionic conductance activated by glutamine, and this conductance is selective for H +. Although SN1 couples amino acid uptake to H + exchange, the glutamine-gated H + conductance is not stoichiometrically coupled to transport. Protons thus permeate SN1 both coupled to and uncoupled from amino acid¯ux, providing novel mechanisms to regulate the transfer of glutamine between cells.

Proceedings of the National Academy of Sciences, 2002

Quantal release of the principal excitatory neurotransmitter glutamate requires a mechanism for i... more Quantal release of the principal excitatory neurotransmitter glutamate requires a mechanism for its transport into secretory vesicles. Within the brain, the complementary expression of vesicular glutamate transporters (VGLUTs) 1 and 2 accounts for the release of glutamate by all known excitatory neurons. We now report the identification of VGLUT3 and its expression by many cells generally considered to release a classical transmitter with properties very different from glutamate. Remarkably, subpopulations of inhibitory neurons as well as cholinergic interneurons, monoamine neurons, and glia express VGLUT3. The dendritic expression of VGLUT3 by particular neurons also indicates the potential for retrograde synaptic signaling. The distribution and subcellular location of VGLUT3 thus suggest novel modes of signaling by glutamate.

Neuroscience, 1986

The glutamate immunoreactivity of different cell popul atio ns was compared quantitatively in the... more The glutamate immunoreactivity of different cell popul atio ns was compared quantitatively in the cerebellar cortex of cat, using an an tiserum raised against glutamate coupled to bovine serum albumin by gl utaraldehyde. Neuronal and glial processes were identified on serial electron microscopic secl ions which were processed by a postembedding immunogold procedure. The surface density of colloidal gold particles was used for statistical comparison of the relative levels of glutamate in cell populations. or in different parts of the same population. The terminals of mossy and parallel fi bres had significantly higher levels of glutamate immunoreactivity than Golgi cell terminals, granule cell dendritic digits, Purkinje cell dendrites or dendritic spines. Golgi cell terminals were identified by their position and GABA immunoreactivity as revealed by immunogold in serial secti ons. The dendritic digits of the putative gl utamatergic granule cells had significantl y higher glutamate immunoreactivity than did Purkinje cell dendrites and dendritic spines. Glial cell processes in the molecular layer had lower level of glutamate immunoreactivity than any of the neuronal processes. The results demonstrate that the highest levels of glutamate immunoreactivity occur in mossy and parallel fibre presynaptic terminals that are known to have an excitatory effect. This supports previous suggestions that glutamate may be a transmitter at these synapses. The measurement of the levels of putative amino acid transmitters in identified neuronal populations, or in different parts of the same popul ation, could have wide applications in studies on the chemical neuroanatomy of the nervous system .

Neurochemical Research, 2007

b-Amyloid (Ab) peptides may cause malfunction and death of neurons in Alzheimer's disease. We inv... more b-Amyloid (Ab) peptides may cause malfunction and death of neurons in Alzheimer's disease. We investigated the effect of Ab on key transporters of amino acid neurotransmission in cells cultured from rat cerebral cortex. The cultures were treated with Ab(25-35) at 3 and 10 lM for 12 and 24 h followed by quantitative analysis of immunofluorescence intensity. In mixed neuronal-glial cell cultures (from P1 rats), Ab reduced the concentration of system A glutamine transporter 1 (SAT1), by up to 50% expressed relative to the neuronal marker microtubuleassociated protein 2 (MAP2) in the same cell. No significant effects were detected on vesicular glutamate transporters VGLUT1 or VGLUT2 in neurons, or on glial system N glutamine transporter 1 (SN1). In neuronal cell cultures (from E18 rats), Ab(25-35) did not reduce SAT1 immunoreactivity, suggesting that the observed effect depends on the presence of astroglia. The results indicate that Ab may impair neuronal function and transmitter synthesis, and perhaps reduce excitotoxicity, through a reduction in neuronal glutamine uptake. Keywords b-Amyloid peptide (25-35) Á Cell culture Á Alzheimer's disease Á Vesicular glutamate transporter Á Glutamine transporter Special issue article in honor of Dr. Frode Fonnum.

Nature Protocols, 2008

An increasing number of imaging techniques are in use to study the localization of molecules invo... more An increasing number of imaging techniques are in use to study the localization of molecules involved in cell-to-cell signaling. Here we describe the use of immunogold procedures to detect and quantify molecules on electron micrographs. To measure the areas of the subcellular compartments under investigation, the protocol uses an overlay screen with an array of regularly spaced points. On the basis of this, the densities of the gold-labeled molecules can be calculated. Despite the limited lateral resolution of the immunogold method as used by many investigators (B30 nm), it is possible to measure the content of molecules associated with tiny tissue compartments, e.g., synaptic vesicles and different types of membrane, such as plasma membranes and vesicle membranes. The quantification protocol can be carried out without using computer programs. The entire protocol can be completed in B15 d.

The Journal of Lipid Research, 2007

Journal of Cell Science, 2004

To elucidate the possible roles of the CNS neurotransmitters glycine and GABA in neuroendocrine p... more To elucidate the possible roles of the CNS neurotransmitters glycine and GABA in neuroendocrine paracrine signalling, we investigated their localizations, and those of their transport proteins, by confocal immunofluorescence and quantitative post-embedding immuno-electron microscopy in the pancreatic islets of Langerhans. We show that A-cells contain glycine in synaptic-like microvesicles as well as in secretory granules. A-cells express the macromolecules necessary to: (1) concentrate glycine within both organelle types before release (the vesicular GABA/glycine transporter VGAT=VIAAT); and to (2) take up the transmitter from the extracellular space (the plasma membrane glycine transporter GLYT2). Also B-cells have glycine in their microvesicles and granules, but the microvesicle/cytosol ratio is lower than in A-cells, consistent with the presence of GABA (which competes with glycine for vesicular uptake) in the cytosol at a much higher concentration in B-cells than in A-cells. Bot...

European Journal of Neuroscience, 2007

Adenosine and ATP, via their specific P1 and P2 receptors, modulate a wide variety of cellular an... more Adenosine and ATP, via their specific P1 and P2 receptors, modulate a wide variety of cellular and tissue functions, playing a neuroprotective or neurodegenerative role in brain damage conditions. Although, in general, adenosine inhibits excitability and ATP functions as an excitatory transmitter in the central nervous system, recent data suggest the existence of a heterodimerization and a functional interaction between P1 and P2 receptors in the brain. In particular, interactions of adenosine A 1 and P2Y 1 receptors may play important roles in the purinergic signalling cascade. In the present work, we investigated the subcellular localization ⁄ colocalization of the receptors and their functional cross-talk at the membrane level in Wistar rat hippocampus. This is a particularly vulnerable brain area, which is sensitive to adenosine-and ATP-mediated control of glutamatergic transmission. The postembedding immunogold electron microscopy technique showed that the two receptors are co-localized at the synaptic membranes and surrounding astroglial membranes of glutamatergic synapses. To investigate the functional cross-talk between the two types of purinergic receptors, we evaluated the reciprocal effects of their activation on their G protein coupling. P2Y 1 receptor stimulation impaired the potency of A 1 receptor coupling to G protein, whereas the stimulation of A 1 receptors increased the functional responsiveness of P2Y 1 receptors. The results demonstrated an A 1-P2Y 1 receptor co-localization at glutamatergic synapses and surrounding astrocytes and a functional interaction between these receptors in hippocampus, suggesting ATP and adenosine can interact in purine-mediated signalling. This may be particularly important during pathological conditions, when large amounts of these mediators are released.

European Journal of Neuroscience, 1994

The purpose of the present study was to evaluate olfactory event-related potentials (OERPs) elici... more The purpose of the present study was to evaluate olfactory event-related potentials (OERPs) elicited by amyl acetate from subjects performing a visuomotor tracking task compared with the no-task conditions of eyes open and eyes closed. Task condition did not produce any reliable effects for any amplitude measure. Task type weakly influenced only P2 latency. Elder adults evinced smaller P2 and N1/P2 amplitudes and longer N1 and P2 latencies than young adults. The results suggest that tracking task performance is not necessary to obtain robust OERPs from normal subjects of a wide age range.