Advances in Experimental Medicine and Biology, 1994
Ammonia intoxication is well known to produce seizures (1). These seizures may be cortical or spi... more Ammonia intoxication is well known to produce seizures (1). These seizures may be cortical or spinal in origin (1,2,3,4,5). Because ammonia predominantly increases the excitability of the spinal cord (1,2), most seizures are probably spinal in origin. The pathophysiology of cortical and spinal seizures induced by ammonia intoxication is not well understood. In addition, it has not been investigated when these spinal seizures occur during the course of ammonia intoxication. This study attempts to elucidate these little understood issues.
Advances in Experimental Medicine and Biology, 1993
Hyperammonemia has two effects on the function of neurons: inactivation of Cl-extrusion and depol... more Hyperammonemia has two effects on the function of neurons: inactivation of Cl-extrusion and depolarization of the resting membrane potential. The consequences of these two effects of hyperammonemia on the function of neurons in mammalians in vivo have been reviewed previously (64,65). In brief, the inactivation of Cl-extrusion shifts the equilibrium potential of the inhibitory postsynaptic potential (IPSP, EIPSP) to the level of the resting membrane potential. Under a certain condition, postsynaptic inhibition occurring at resting membrane potential, i.e., “gate-inhibition”, postsynaptic inhibition cannot suppress neuronal excitation. However, when postsynaptic inhibition occurs while the neuron is temporarily depolarized, i.e., “break-inhibition”, the efficacy of postsynaptic inhibition shows no significant impairment. The inactivation of Cl-extrusion from neurons occurs without signs of changes in the effects of synaptically released GABA or glycine on neurons, and without changes in excitatory synaptic transmission. The inactivation of Cl-extrusion and resulting dysfunction of gate-inhibition is sufficient to produce in experimental animals changes of the EEG. The brain tissue levels of NH4 + necessary to inactivate Cl-extrusion and to produce encephalopathy in experimental animals are both in the same range, i.e., 0.7–1.3 mM. Therefore, it was suggested that the encephalopathy due to hyperammonemia is caused, or at least significantly contributed to, by the inactivation of Cl-extrusion from neurons.
When intracellular recordings from cortical neurons became available it was obvious to most worke... more When intracellular recordings from cortical neurons became available it was obvious to most workers in this field that a relationship exists especially between the postsynaptic potentials and the potential recorded from the cortical surface (Kandel and Spencer 1961, Li and Chou 1962, Lux and Klee 1962, Creutzfeldt et al. 1964, Pollen 1964, Purpura et al. 1964, Jasper and Stefanis 1965) in accord-ance with an earlier hypothesis of Eccles (1951). In the neocortex, the postsynaptic activity of pyramidal tract (PT) cells was assumed to govern the generation of the electrocorticogram and special consideration in this respect was given to the localization of excitatory and inhibitory synapses on the nerve cell soma and apical dendrite (Eccles 1951, Creutzfeldt et al. 1966). In a more recent study by Humphrey (1968), evidence was presented for a causal relationship between the postsynaptic effects of synchronous recurrent activity of PT cells with the antidromically evoked surface potentia...
BACKGROUND In clinical practice, small myelinated sensory fibers conveying pain and other sensati... more BACKGROUND In clinical practice, small myelinated sensory fibers conveying pain and other sensations, Aδ-fibers, cannot be examined with available nerve conduction study techniques. NEW METHOD Equipment available in clinical neurophysiology laboratories is used to record from human sensory nerves multiple averaged responses to non-painful stimulation of intraepidermal nerves. Ten averaged responses are analyzed in all possible pair combinations with an algorithm applied to a 0.45 ms period of amplitude and frequency (power spectrum). The median of the algorithms is compared to control data to identify potentials generated as response to intraepidermal stimulation. RESULTS Median analysis of the algorithm applied to amplitude and frequency of multiple record pairs identifies potentials with conduction velocities of Aδ-fibers. The analysis of frequency (power spectrum) adds data to the analysis of amplitude. Median analysis of multiple record pairs yields more data than analysis of one pair of alternate averages with the same algorithm. COMPARISON WITH EXISTING METHOD(S) At present, analysis of one pair of alternate average records with an algorithm is the only method to identify Aδ-fiber generated potentials. Median analysis of the same algorithm applied to the amplitude of multiple record pairs increases the number of Aδ-fiber generated potentials identified. Neither median analysis of amplitude nor frequency of multiple records pairs has ever been used for conduction studies of nerve fibers, including Aδ-fibers. CONCLUSIONS Stimulation, recording and data analysis methods used in this study can be applied in the clinical EMG laboratory to identify the conduction velocities of Aδ-fibers in human sensory nerves.
1. Glutamine is thought to be a precursor of the pool of glutamate that is used as synaptic trans... more 1. Glutamine is thought to be a precursor of the pool of glutamate that is used as synaptic transmitter. NH4+ inhibits glutaminase, the enzyme presumed to cleave glutamine into glutamate in synaptic terminals. Therefore a decrease by NH4+ of excitatory synaptic transmission in hippocampus was suggested to be due to the inability to utilize glutamine as a precursor for glutamate and subsequent transmitter depletion. This study reexamines the effects of NH4+ on excitatory synaptic transmission. 2. The effects of NH4+ on excitatory synaptic transmission from low-threshold afferent fibers, presumably Ia-afferent fibers, to motoneurons was investigated in the spinal cord of anesthetized cats in vivo. 3. Action potentials of low-threshold afferent fibers were recorded at the entry of the dorsal roots into the spinal cord. An extracellular electrode within a motoneuron nucleus recorded the action potential of low-threshold afferent fibers and the extracellular monosynaptic excitatory posts...
Hepatic encephalopathy is a potentially reversible disease. Therefore, a structural abnormality o... more Hepatic encephalopathy is a potentially reversible disease. Therefore, a structural abnormality of the CNS cannot be the cause of the encephalopathy. The encephalopathy is the expression of an abnormal function, or dysfunction, of the CNS. Since the CNS consists of neuronal circuits, a dysfunction of these neuronal circuits underlies the dysfunction of the CNS. Neuronal circuits consist of individual neurons which must function normally to properly interact with each other. Hence it can be presumed that the cause of encephalopathy is a dysfunction of individual neurons, which disturbs interactions between individual neurons in neuronal circuits, causes a dysfunction of neuronal circuits, and causes a dysfunction of the CNS.
The action of intravenously administered diazepam (Valium) on postsynaptic inhibition was studied... more The action of intravenously administered diazepam (Valium) on postsynaptic inhibition was studied in cat motor cortex. The efficacy of postsynaptic inhibition of pyramidal tract cells was measured as the ability to suppress action potential generation. Diazepam increased the suppression of action potentials by inhibition. This effect may explain the anticonvulsant action of diazepam.
1. In deeply barbiturate-anesthetized animals. NH4+ decreases spinal excitatory synaptic transmis... more 1. In deeply barbiturate-anesthetized animals. NH4+ decreases spinal excitatory synaptic transmission by neuronal depolarization and subsequent block of conduction of action potentials into presynaptic terminals of low-threshold (presumably Ia-) afferents. Because barbiturates by themselves depress excitatory synaptic transmission and may have modified the effects of NH4+, this study examines the effect of NH4+ on excitatory synaptic transmission in the unanesthetized animal. 2. The effects of NH4+ on monosynaptic and polysynaptic excitatory reflexes as well as di- and polysynaptic inhibition were investigated in the spinal cord of the decerebrate and unanesthetized cat in vivo. 3. The monosynaptic excitatory reflex (MSR) elicited by muscle nerve stimulation and polysynaptic excitatory reflexes elicited by muscle (MSR-PSR) or cutaneous nerve stimulation (Cut-PSR) were recorded from the ventral roots L7 or S1. The P-wave was recorded from the cord dorsum. Di- and polysynaptic inhibit...
1. Transmitter glutamate is thought to be derived from glutamine via cleavage by glutaminase. NH+... more 1. Transmitter glutamate is thought to be derived from glutamine via cleavage by glutaminase. NH+4 inhibits glutaminase. Therefore the decrease of glutamatergic excitatory synaptic transmission by NH+4 was thought to be due to the inability of glutamine to serve as precursor for glutamate. However, in cat spinal cord, NH+4 abolished excitatory synaptic transmission by a conduction block for action potentials in presynaptic terminals. The conduction block prevented inferences as to the effects of NH+4 on the availability of glutamate for synaptic transmission. This study reexamines the effects of NH+4 on glutamatergic excitatory synaptic transmission in cerebellar neurons in tissue culture. 2. Whole-cell patch voltage-clamp recordings were obtained from presumed Purkinje cells. Extracellular stimulation of presumed granule cells produced mono- and polysynaptic excitatory postsynaptic currents (EPSCs). In addition, presumed Purkinje cells showed spontaneous EPSCs that occurred indepen...
The effect of intravenously administered ammonium salts on postsynaptic inhibition of pyramidal t... more The effect of intravenously administered ammonium salts on postsynaptic inhibition of pyramidal tract cells was investigated in cat motor cortex. Extracellular recordings revealed that pyramidally or thalamically mediated inhibition of antidromic action potentials is abolished by ammonia. Intracellular recordings demonstrated that hyperpolarizing IPSPs vanished and EPSPs appeared while the inhibitory stimuli still triggered a decrease of neuronal resistance and the resting membrane potential was unchanged. It is concluded that ammonia disinhibited action-potential generation and EPSPs by shifting E(IPSP) to the level of the resting membrane potential. With disinhibition and facilitation replacing inhibitation of action potentials, ammonia clearly disturbs those cortical functions involving postsynaptic inhibition.
The clinical features of four families with autosomal dominant spastic paraparesis (FSP) are desc... more The clinical features of four families with autosomal dominant spastic paraparesis (FSP) are described, along with the results of linkage analysis to markers from the regions of chromosomes 2, 14, and 15 which are known to contain spastic paraplegia genes. All families had 'pure' spastic paraparesis (FSP), but the severity of symptoms varied widely among families, and other mild neurologic signs were observed in some subjects. Although no family individually yielded a lod score >3.0, all families yielded positive lod scores with chromosome 2 markers, and a maximal lod score of 5.7 was obtained for the families combined using marker D2S352. There was no evidence of linkage to chromosome 14 or 15 in any of the families.
Ammonia intoxication abolished the suppression of action potential generation by cortical postsyn... more Ammonia intoxication abolished the suppression of action potential generation by cortical postsynaptic inhibition due to the inactivation of neuronal C1-extrusion. The disinhibition by ammonia intoxication occurred when ammonia concentrations in the cerebral cortex were increased to 320 % of normal. Fluoroacetate poisoning and insulin-induced hypoglycemia, which are known to increase ammonia concentrations in the CNS and previously have been shown to inactivate CI-extrusion in spinal motoneurons, abolished the suppression of action potential generation by cortical postsynaptic inhibition like ammonia intoxication. This disinhibition occurred at unchanged cerebral ammonia concentrations. The effect of fluoroacetate and insulininduced hypoglycemia on cortical postsynaptic inhibition is either due to a direct, i.e. not ammonia mediated, inactivation of neuronal CI-extrusion or due to a disturbance of the synaptic mechanisms mediated by the transmitter of cortical inhibition, GABA. Toxic-metabolic encephalopathies which increase cerebral ammonia concentrations beyond 320 % of normal may produce a dysfunction of the CNS due to inactivation of neuronal C1-extrusion leading to ineffective cortical inhibition. However, in fluoroacetate poisoning and insulin-induced hypoglycemia increased ammonia concentrations in the CNS have only a secondary role in initiating a dysfunction of the CNS since disinhibition occurs before ammonia concentrations increase.
Advances in Experimental Medicine and Biology, 1994
Ammonia intoxication is well known to produce seizures (1). These seizures may be cortical or spi... more Ammonia intoxication is well known to produce seizures (1). These seizures may be cortical or spinal in origin (1,2,3,4,5). Because ammonia predominantly increases the excitability of the spinal cord (1,2), most seizures are probably spinal in origin. The pathophysiology of cortical and spinal seizures induced by ammonia intoxication is not well understood. In addition, it has not been investigated when these spinal seizures occur during the course of ammonia intoxication. This study attempts to elucidate these little understood issues.
Advances in Experimental Medicine and Biology, 1993
Hyperammonemia has two effects on the function of neurons: inactivation of Cl-extrusion and depol... more Hyperammonemia has two effects on the function of neurons: inactivation of Cl-extrusion and depolarization of the resting membrane potential. The consequences of these two effects of hyperammonemia on the function of neurons in mammalians in vivo have been reviewed previously (64,65). In brief, the inactivation of Cl-extrusion shifts the equilibrium potential of the inhibitory postsynaptic potential (IPSP, EIPSP) to the level of the resting membrane potential. Under a certain condition, postsynaptic inhibition occurring at resting membrane potential, i.e., “gate-inhibition”, postsynaptic inhibition cannot suppress neuronal excitation. However, when postsynaptic inhibition occurs while the neuron is temporarily depolarized, i.e., “break-inhibition”, the efficacy of postsynaptic inhibition shows no significant impairment. The inactivation of Cl-extrusion from neurons occurs without signs of changes in the effects of synaptically released GABA or glycine on neurons, and without changes in excitatory synaptic transmission. The inactivation of Cl-extrusion and resulting dysfunction of gate-inhibition is sufficient to produce in experimental animals changes of the EEG. The brain tissue levels of NH4 + necessary to inactivate Cl-extrusion and to produce encephalopathy in experimental animals are both in the same range, i.e., 0.7–1.3 mM. Therefore, it was suggested that the encephalopathy due to hyperammonemia is caused, or at least significantly contributed to, by the inactivation of Cl-extrusion from neurons.
When intracellular recordings from cortical neurons became available it was obvious to most worke... more When intracellular recordings from cortical neurons became available it was obvious to most workers in this field that a relationship exists especially between the postsynaptic potentials and the potential recorded from the cortical surface (Kandel and Spencer 1961, Li and Chou 1962, Lux and Klee 1962, Creutzfeldt et al. 1964, Pollen 1964, Purpura et al. 1964, Jasper and Stefanis 1965) in accord-ance with an earlier hypothesis of Eccles (1951). In the neocortex, the postsynaptic activity of pyramidal tract (PT) cells was assumed to govern the generation of the electrocorticogram and special consideration in this respect was given to the localization of excitatory and inhibitory synapses on the nerve cell soma and apical dendrite (Eccles 1951, Creutzfeldt et al. 1966). In a more recent study by Humphrey (1968), evidence was presented for a causal relationship between the postsynaptic effects of synchronous recurrent activity of PT cells with the antidromically evoked surface potentia...
BACKGROUND In clinical practice, small myelinated sensory fibers conveying pain and other sensati... more BACKGROUND In clinical practice, small myelinated sensory fibers conveying pain and other sensations, Aδ-fibers, cannot be examined with available nerve conduction study techniques. NEW METHOD Equipment available in clinical neurophysiology laboratories is used to record from human sensory nerves multiple averaged responses to non-painful stimulation of intraepidermal nerves. Ten averaged responses are analyzed in all possible pair combinations with an algorithm applied to a 0.45 ms period of amplitude and frequency (power spectrum). The median of the algorithms is compared to control data to identify potentials generated as response to intraepidermal stimulation. RESULTS Median analysis of the algorithm applied to amplitude and frequency of multiple record pairs identifies potentials with conduction velocities of Aδ-fibers. The analysis of frequency (power spectrum) adds data to the analysis of amplitude. Median analysis of multiple record pairs yields more data than analysis of one pair of alternate averages with the same algorithm. COMPARISON WITH EXISTING METHOD(S) At present, analysis of one pair of alternate average records with an algorithm is the only method to identify Aδ-fiber generated potentials. Median analysis of the same algorithm applied to the amplitude of multiple record pairs increases the number of Aδ-fiber generated potentials identified. Neither median analysis of amplitude nor frequency of multiple records pairs has ever been used for conduction studies of nerve fibers, including Aδ-fibers. CONCLUSIONS Stimulation, recording and data analysis methods used in this study can be applied in the clinical EMG laboratory to identify the conduction velocities of Aδ-fibers in human sensory nerves.
1. Glutamine is thought to be a precursor of the pool of glutamate that is used as synaptic trans... more 1. Glutamine is thought to be a precursor of the pool of glutamate that is used as synaptic transmitter. NH4+ inhibits glutaminase, the enzyme presumed to cleave glutamine into glutamate in synaptic terminals. Therefore a decrease by NH4+ of excitatory synaptic transmission in hippocampus was suggested to be due to the inability to utilize glutamine as a precursor for glutamate and subsequent transmitter depletion. This study reexamines the effects of NH4+ on excitatory synaptic transmission. 2. The effects of NH4+ on excitatory synaptic transmission from low-threshold afferent fibers, presumably Ia-afferent fibers, to motoneurons was investigated in the spinal cord of anesthetized cats in vivo. 3. Action potentials of low-threshold afferent fibers were recorded at the entry of the dorsal roots into the spinal cord. An extracellular electrode within a motoneuron nucleus recorded the action potential of low-threshold afferent fibers and the extracellular monosynaptic excitatory posts...
Hepatic encephalopathy is a potentially reversible disease. Therefore, a structural abnormality o... more Hepatic encephalopathy is a potentially reversible disease. Therefore, a structural abnormality of the CNS cannot be the cause of the encephalopathy. The encephalopathy is the expression of an abnormal function, or dysfunction, of the CNS. Since the CNS consists of neuronal circuits, a dysfunction of these neuronal circuits underlies the dysfunction of the CNS. Neuronal circuits consist of individual neurons which must function normally to properly interact with each other. Hence it can be presumed that the cause of encephalopathy is a dysfunction of individual neurons, which disturbs interactions between individual neurons in neuronal circuits, causes a dysfunction of neuronal circuits, and causes a dysfunction of the CNS.
The action of intravenously administered diazepam (Valium) on postsynaptic inhibition was studied... more The action of intravenously administered diazepam (Valium) on postsynaptic inhibition was studied in cat motor cortex. The efficacy of postsynaptic inhibition of pyramidal tract cells was measured as the ability to suppress action potential generation. Diazepam increased the suppression of action potentials by inhibition. This effect may explain the anticonvulsant action of diazepam.
1. In deeply barbiturate-anesthetized animals. NH4+ decreases spinal excitatory synaptic transmis... more 1. In deeply barbiturate-anesthetized animals. NH4+ decreases spinal excitatory synaptic transmission by neuronal depolarization and subsequent block of conduction of action potentials into presynaptic terminals of low-threshold (presumably Ia-) afferents. Because barbiturates by themselves depress excitatory synaptic transmission and may have modified the effects of NH4+, this study examines the effect of NH4+ on excitatory synaptic transmission in the unanesthetized animal. 2. The effects of NH4+ on monosynaptic and polysynaptic excitatory reflexes as well as di- and polysynaptic inhibition were investigated in the spinal cord of the decerebrate and unanesthetized cat in vivo. 3. The monosynaptic excitatory reflex (MSR) elicited by muscle nerve stimulation and polysynaptic excitatory reflexes elicited by muscle (MSR-PSR) or cutaneous nerve stimulation (Cut-PSR) were recorded from the ventral roots L7 or S1. The P-wave was recorded from the cord dorsum. Di- and polysynaptic inhibit...
1. Transmitter glutamate is thought to be derived from glutamine via cleavage by glutaminase. NH+... more 1. Transmitter glutamate is thought to be derived from glutamine via cleavage by glutaminase. NH+4 inhibits glutaminase. Therefore the decrease of glutamatergic excitatory synaptic transmission by NH+4 was thought to be due to the inability of glutamine to serve as precursor for glutamate. However, in cat spinal cord, NH+4 abolished excitatory synaptic transmission by a conduction block for action potentials in presynaptic terminals. The conduction block prevented inferences as to the effects of NH+4 on the availability of glutamate for synaptic transmission. This study reexamines the effects of NH+4 on glutamatergic excitatory synaptic transmission in cerebellar neurons in tissue culture. 2. Whole-cell patch voltage-clamp recordings were obtained from presumed Purkinje cells. Extracellular stimulation of presumed granule cells produced mono- and polysynaptic excitatory postsynaptic currents (EPSCs). In addition, presumed Purkinje cells showed spontaneous EPSCs that occurred indepen...
The effect of intravenously administered ammonium salts on postsynaptic inhibition of pyramidal t... more The effect of intravenously administered ammonium salts on postsynaptic inhibition of pyramidal tract cells was investigated in cat motor cortex. Extracellular recordings revealed that pyramidally or thalamically mediated inhibition of antidromic action potentials is abolished by ammonia. Intracellular recordings demonstrated that hyperpolarizing IPSPs vanished and EPSPs appeared while the inhibitory stimuli still triggered a decrease of neuronal resistance and the resting membrane potential was unchanged. It is concluded that ammonia disinhibited action-potential generation and EPSPs by shifting E(IPSP) to the level of the resting membrane potential. With disinhibition and facilitation replacing inhibitation of action potentials, ammonia clearly disturbs those cortical functions involving postsynaptic inhibition.
The clinical features of four families with autosomal dominant spastic paraparesis (FSP) are desc... more The clinical features of four families with autosomal dominant spastic paraparesis (FSP) are described, along with the results of linkage analysis to markers from the regions of chromosomes 2, 14, and 15 which are known to contain spastic paraplegia genes. All families had 'pure' spastic paraparesis (FSP), but the severity of symptoms varied widely among families, and other mild neurologic signs were observed in some subjects. Although no family individually yielded a lod score >3.0, all families yielded positive lod scores with chromosome 2 markers, and a maximal lod score of 5.7 was obtained for the families combined using marker D2S352. There was no evidence of linkage to chromosome 14 or 15 in any of the families.
Ammonia intoxication abolished the suppression of action potential generation by cortical postsyn... more Ammonia intoxication abolished the suppression of action potential generation by cortical postsynaptic inhibition due to the inactivation of neuronal C1-extrusion. The disinhibition by ammonia intoxication occurred when ammonia concentrations in the cerebral cortex were increased to 320 % of normal. Fluoroacetate poisoning and insulin-induced hypoglycemia, which are known to increase ammonia concentrations in the CNS and previously have been shown to inactivate CI-extrusion in spinal motoneurons, abolished the suppression of action potential generation by cortical postsynaptic inhibition like ammonia intoxication. This disinhibition occurred at unchanged cerebral ammonia concentrations. The effect of fluoroacetate and insulininduced hypoglycemia on cortical postsynaptic inhibition is either due to a direct, i.e. not ammonia mediated, inactivation of neuronal CI-extrusion or due to a disturbance of the synaptic mechanisms mediated by the transmitter of cortical inhibition, GABA. Toxic-metabolic encephalopathies which increase cerebral ammonia concentrations beyond 320 % of normal may produce a dysfunction of the CNS due to inactivation of neuronal C1-extrusion leading to ineffective cortical inhibition. However, in fluoroacetate poisoning and insulin-induced hypoglycemia increased ammonia concentrations in the CNS have only a secondary role in initiating a dysfunction of the CNS since disinhibition occurs before ammonia concentrations increase.
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