Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026827 (hypotonia)
 5,860 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate whether prolonged severe swelling would cause irreversible injury to neurons, we exposed hippocampal tissue slices to hypotonic solutions (142 mosmol/kg) and followed the recovery of evoked responses for 5 h. Orthodromically evoked responses increased during hypotonia, except during recurrent waves of spreading depression (SD). After restoring normal osmotic pressure (pi o), evoked potentials became profoundly depressed. Following 30 min exposure, nearly maximal orthodromic responses recovered completely but responses to submaximal stimuli remained depressed, indicating elevated threshold. Following 60 min exposure, orthodromic transmission remained depressed. In slices from young animals, antidromic population spikes recovered completely, but in slices from older rats they remained partly depressed. Withdrawing calcium and raising magnesium concentration before and during hypotonic exposure resulted in modest but significant improvement of the recovery of synaptically transmitted responses, but made no difference for antidromic responses. With [Ca2+]o reduced and [Mg2+]o elevated, electrographic seizures replaced the episodes of SD during low pi o treatment. We conclude that even 60 min of severe hypotonic swelling did not kill CA1 pyramidal cells in tissue from young rats, but in its aftermath synaptic transmission was disrupted. Uptake of calcium may have played a minor role in the impairment of synaptic transmission. We propose hypothetically that post-hypotonic shrinkage of dendrites disrupted the integrity of excitatory synapses.
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PMID:The extent and mechanism of the loss of function caused by strongly hypotonic solutions in rat hippocampal slices. 855 31

Low extracellular osmotic pressure (pi o) is known to enhance CNS responsiveness and the chance of seizures, but the mechanism of the hyperexcitability is not clear. We recorded evoked potentials in st. radiatum and st. pyramidale of CA1. Tissue electrical resistance (Ro) was determined from the voltage drop (VRo) evoked by constant current pulses. Lowering of pi o by reducing [NaCl] caused a concentration-dependent increase of amplitude and duration of extracellular excitatory postsynaptic potentials (fEPSPs). fEPSPs increased much more than did VRo, but antidromic population spikes increased in proportion to VRo. fEPSP increased also in isosmotic low NaCl (fructose or mannitol substituted) solutions, but not as much as in low pi o. In moderately hypotonic solutions orthodromic population spikes increased as expected from the augmented fEPSP, but in strong hypotonia input-output curves shifted to the left and single stimuli evoked multiple population spikes, indicating lowering of threshold of postsynaptic neurons. Blocking N-methyl-D-aspartate (NMDA) receptors did not diminish the enhancement of fEPSP amplitude. Spreading depression (SD) erupted in most slices in very low pi o, but not in isoosmotic low [NaCl] solutions. We conclude that the hypotonic enhancement of EPSPs depends, in part, on the lowering of [Na+]o and/or of [Cl-]o, and it may be augmented by dendritic swelling favoring electrotonic spread of EPSPs from dendrites to somata, and buildup of transmitter concentration due to swelling of perisynaptic glia. SD can be initiated by cell swelling, but the depolarization associated with SD is probably not caused by the opening of stretch-gated ion channels.
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PMID:Hypotonic exposure enhances synaptic transmission and triggers spreading depression in rat hippocampal tissue slices. 855 32

Intrinsic optical signals (IOSs) induced by synaptic stimulation and moderate hypotonic swelling in brain tissue slices consist of reduced light scattering and are usually attributed to cell swelling. During spreading depression (SD), however, light-scattering increases even though SD has been shown to cause strong cell swelling. To understand this phenomenon, we recorded extracellular voltage, light transmission (LT), which is inversely related to light scattering, and interstitial volume (ISV) simultaneously from the same site (stratum radiatum of CA1) in both interface and submerged hippocampal slices. As expected, moderate lowering of bath osmolarity caused concentration-dependent shrinkage of ISV and increase in LT, while increased osmolarity induced opposite changes in both variables. During severe hypotonia, however, after an initial increase of LT, the direction of the IOS reversed to a progressive decrease in spite of continuing ISV shrinkage. SD caused by hypotonia, by microinjection of high-K(+) solution, or by hypoxia, was associated with a pronounced LT decrease, during which ISV shrinkage indicated maximal cell swelling. If most of the extracellular Cl(-) was substituted by the impermeant anion methylsulfate and also in strongly hypertonic medium, the SD-related decrease in LT was suppressed and replaced by a monotonic increase. Nevertheless, the degree of ISV shrinkage was similar in low and in normal Cl(-) conditions. The optical signals and ISV changes were qualitatively identical in interface and submerged slices. We conclude that there are at least two mechanisms that underlie reversible optical responses in hippocampal slices. The first mechanism underlies light-scattering decrease (hence enhancing LT) when ISV shrinks (cell swelling) under synaptic stimulation and mild hypotonia. Similarly, as result of this mechanism, expansion of ISV (cell shrinkage) during mild hypertonia leads to an increased light scattering (and decreased LT). Thus optical signals associated with this first mechanism show expected cell-volume changes and are linked to either cell swelling or shrinkage. A different mechanism causes the light-scattering increase (leading to a LT decrease) during severe hypotonia and various forms of SD but with a severely decreased ISV. This second mechanism may be due to organelle swelling or dendritic beading but not to cell-volume increase. These two mechanisms can summate, indicating that they are independent in origin. Suppression of the SD-related light-scattering increase by lowering [Cl(-)](o) or severe hypertonia unmasks the underlying swelling-related scattering decrease. The simultaneous IOS and ISV measurements clearly distinguish these two mechanisms of optical signal generation.
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PMID:Two different mechanisms underlie reversible, intrinsic optical signals in rat hippocampal slices. 1192 12

Glycine serves a dual role in neurotransmission. It is the primary inhibitory neurotransmitter in the spinal cord and brain stem and is also an obligatory coagonist at the excitatory glutamate, N-methyl-D-aspartate receptor (NMDAR). Therefore, the postsynaptic action of glycine should be strongly regulated to maintain a balance between its inhibitory and excitatory inputs. The glycine concentration at the synapse is tightly regulated by two types of glycine transporters, GlyT1 and GlyT2, located on nerve terminals or astrocytes. Genetic studies demonstrated that homozygous (GlyT1-/-) newborn mice display severe sensorimotor deficits characterized by lethargy, hypotonia, and hyporesponsivity to tactile stimuli and ultimately die in their first postnatal day. These symptoms are similar to those associated with the human disease glycine encephalopathy in which there is a high level of glycine in cerebrospinal fluid of affected individuals. The purpose of this investigation is to determine the impact of chronically high concentrations of endogenous glycine on glutamatergic neurotransmission during postnatal development using an in vivo mouse model (GlyT1+/-). The results of our study indicate the following; that compared with wild-type mice, CA1 pyramidal neurons from mutants display significant disruptions in hippocampal glutamatergic neurotransmission, as suggested by a faster kinetic of NMDAR excitatory postsynaptic currents, a lower reduction of the amplitude of NMDAR excitatory postsynaptic currents by ifenprodil, no difference in protein expression for NR2A and NR2B but a higher protein expression for PSD-95, an increase in their number of synapses and finally, enhanced neuronal excitability.
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PMID:Chronically saturating levels of endogenous glycine disrupt glutamatergic neurotransmission and enhance synaptogenesis in the CA1 region of mouse hippocampus. 2163 74

Pur-alpha is a highly conserved sequence-specific DNA and RNA binding protein with established roles in DNA replication, RNA translation, cell cycle regulation, and maintenance of neuronal differentiation. Prior studies have shown that mice lacking Pur-alpha (-/-) display decreased neurogenesis and impaired neuronal differentiation. We sought to examine for the first time, the behavioral phenotype and brain histopathology of mice that are heterozygous (+/-) for Pur-alpha. Standardized behavioral phenotyping revealed a decreased escape response to touch, limb and abdominal hypotonia, and gait abnormalities in heterozygous Pur-alpha (+/-) mice, compared to wild-type (+/+) littermates. Footprint pattern analyses showed wider-based steps, increased missteps and more outwardly rotated hindpaws in heterozygous Pur-alpha (+/-) mice, suggestive of cerebellar pathology. The Barnes maze and novel object location testing revealed significant memory deficits in heterozygous Pur-alpha mice, suggestive of hippocampal pathology. Quantitative immunohistochemical assays of the vermal region of the cerebellum and CA1-3 regions of the hippocampus revealed reduced numbers of neurons in general, as well as reduced numbers of Pur-alpha+-immunopositive neurons and dendrites in heterozygous Pur-alpha mice, compared to wild-type littermates. Past studies have implicated mutations in Pur-alpha in several diseases of brain development and neurodegeneration. When combined with these new findings, the Pur-alpha heterozygous knockout mice may provide an animal model to study mechanisms of and treatments for Pur-alpha-related cognitive deficiencies and neuropathology.
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PMID:Memory deficits, gait ataxia and neuronal loss in the hippocampus and cerebellum in mice that are heterozygous for Pur-alpha. 2765 Nov 47