Sodium signals in cerebellar Purkinje neurons and Bergmann glial cells evoked by glutamatergic synaptic transmission.

Glial cells express specific high-affinity transporters for glutamate that play a central role in glutamate clearance at excitatory synapses in the brain. These transporters are electrogenic and are mainly energized by the electrochemical gradient for sodium. In the present study, we combined somatic whole-cell patch-clamp recordings with quantitative Na+ imaging in fine cellular branches of cerebellar Bergmann glial cells and in dendrites of Purkinje neurons to analyze intracellular Na+ signals close to activated synapses. We demonstrate that pressure application of glutamate and glutamate agonists causes local Na+ signals in the mM range. Furthermore, we analyzed the pharmacological profile, as well as the time course and spatial distribution of Na+ signals following short synaptic burst stimulation of parallel or climbing fibers. While parallel fibers stimulation resulted in local sodium transients that were largest in processes close to the stimulation pipette, climbing fibers stimulation elicited global sodium transients throughout the entire cell. Glial sodium signals amounted to several mM, were mainly caused by sodium influx following inward transport of glutamate and persisted for tens of seconds. Sodium transients in dendrites of Purkinje neurons, in contrast, were mainly caused by activation of AMPA receptors and had much faster kinetics. By reducing the driving force for sodium-dependent glutamate uptake, intracellular sodium accumulation in glial cells upon repetitive activity might provide a negative feedback mechanism, promoting the diffusion of glutamate and the activation of extrasynaptic glutamate receptors at active synapses in the cerebellum.

Comparative analysis of anxiety-like behaviors and sensorimotor functions in two rat mutants, ci2 and ci3, with lateralized rotational behavior.

There is increasing evidence that developmental anomalies of cerebral asymmetry are involved in the etiology of psychiatric disorders, including schizophrenia, depression and anxiety. Thus, rodents with abnormal cerebral lateralization are interesting tools to study the association between such anomalies and behavioral dysfunction. The most studied indicator of cerebral asymmetry in the rat is that of circling or rotational behavior. We have recently described two rat mutants, ci2 and ci3, in which lateralized rotational behavior occurs either spontaneously or in response to external stimuli, such as new environment or handling. While cochlear and vestibular defects are found in 52 rats, ci3 rats do not exhibit any inner ear abnormalities. The abnormal motor response to external stimuli raised the possibility that the circling rat mutants may be more likely to express anxiety-related behavior in tests of emotionality. In the present study, we characterized anxiety-related behaviors of ci2 and ci3 rats in the open field, elevated plus-maze and light/dark exploration test. Furthermore, sensorimotor functions of these rats were evaluated by the rotarod, accelerod and wire hang tests. Heterozygous (ci2/+) littermates or rats of the respective background strains (LEW, BH.7A) were used as controls. In contrast to our expectation, both mutants demonstrated less anxiety-related behavior than controls in tests of emotionality. Ci3 rats exhibited normal sensorimotor functions, whereas marked impairment was observed in ci2 rats, which is most likely a consequence of the vestibular dysfunction in these animals. The acoustic startle response (ASR) and prepulse inhibition of ASR did not differ between ci3 rats and controls. The reduced emotionality of the mutant rats indicated by the present experiments may not be specifically linked to anxiety per se, but is maybe more reflective of impulsivity or the inability to normally perceive or process potentially threatening situations. Based on previous findings of dysfunctions of the central dopamine system in ci2 and ci3 mutant rats, we assume that alterations in dopaminergic activity are involved in the maladaptive behavior observed in the present study.

Decreased density of amygdaloid parvalbumin-positive interneurons and behavioral changes in dystonic hamsters (Mesocricetus auratus).

The dtsz hamster represents a model of primary paroxysmal nonkinesiogenic dyskinesia in which dystonic episodes can be induced by stress and anxious stimuli. This disease is regarded as a basal ganglia disorder. In fact, a deficit of striatal interneurons could play a key role in the pathophysiology in dystonic hamsters. Because the involvement of limbic structures cannot be excluded so far, the density of parvalbumin-immunoreactive (PV+) interneurons was determined in the basolateral amygdala in the present study. Compared with nondystonic hamsters, the density of PV+ interneurons was moderately decreased in the dtsz mutant. The functional consequence of this finding was examined by behavioral analyses. Examinations in the elevated plus maze and in a modified open field failed to disclose an enhanced anxiety-related behavior in dtsz hamsters (Mesocricetus auratus). A lower acoustic startle response and a stronger habituation in mutant hamsters than in controls correlated with a decreased body weight. Interestingly, prepulse inhibition was absent in mutant hamsters. The latter finding suggests a disturbed sensorimotor gating that can be related to alterations in both the basal ganglia nuclei and in limbic structures.

Comparative analysis of anxiety-like behaviors and sensorimotor functions in two rat mutants, ci2 and ci3, with lateralized rotational behavior.

There is increasing evidence that developmental anomalies of cerebral asymmetry are involved in the etiology of psychiatric disorders, including schizophrenia, depression and anxiety. Thus, rodents with abnormal cerebral lateralization are interesting tools to study the association between such anomalies and behavioral dysfunction. The most studied indicator of cerebral asymmetry in the rat is that of circling or rotational behavior. We have recently described two rat mutants, ci2 and ci3, in which lateralized rotational behavior occurs either spontaneously or in response to external stimuli, such as new environment or handling. While cochlear and vestibular defects are found in ci2 rats, ci3 rats do not exhibit any inner ear abnormalities. The abnormal motor response to external stimuli raised the possibility that the circling rat mutants may be more likely to express anxiety-related behavior in tests of emotionality. In the present study, we characterized anxiety-related behaviors of ci2 and ci3 rats in the open field, elevated plus-maze and light/dark exploration test. Furthermore, sensorimotor functions of these rats were evaluated by the rotarod, accelerod and wire hang tests. Heterozygous (ci2/+) littermates or rats of the respective background strains (LEW, BH.7A) were used as controls. In contrast to our expectation, both mutants demonstrated less anxiety-related behavior than controls in tests of emotionality. Ci3 rats exhibited normal sensorimotor functions, whereas marked impairment was observed in ci2 rats, which is most likely a consequence of the vestibular dysfunction in these animals. The acoustic startle response (ASR) and prepulse inhibition of ASR did not differ between ci3 rats and controls. The reduced emotionality of the mutant rats indicated by the present experiments may not be specifically linked to anxiety per se, but is maybe more reflective of impulsivity or the inability to normally perceive or process potentially threatening situations. Based on previous findings of dysfunctions of the central dopamine system in ci2 and ci3 mutant rats, we assume that alterations in dopaminergic activity are involved in the maladaptive behavior observed in the present study.

Neonatal medial prefrontal cortex lesion enhances the sensitivity of the mesoaccumbal dopamine system.

Neurodevelopmental models of schizophrenia posit that early brain damage leads to dys- or misconnection effects possibly altering synaptic transmission in brain sites distal of the lesion. We tested the hypothesis that neonatal medial prefrontal cortex (mPFC) lesions affect the sensitivity of the mesoaccumbal dopamine (DA) system. Using extracellular single-unit recordings combined with systemic application of the DA agonist apomorphine, followed by the D2 receptor antagonist haloperidol or the D1 receptor antagonist SCH23390, we compared electrophysiological properties of nucleus accumbens core and shell neurons after bilateral excitotoxic lesions of mPFC induced at postnatal day 7 or in adult rats. Whereas animals with adult mPFC lesions showed an altered discharge pattern within the core region, neonatal mPFC lesions altered the discharge pattern within the shell region. Subcutaneous administration of apomorphine (4 mg/kg) reduced accumbal firing rate in 77% of all neurons. Onset and magnitude of apomorphine-induced inhibition of neuronal activity was faster and stronger in rats with neonatal but not adult mPFC lesions in both core and shell regions. Apomorphine-induced inhibition was partially reversed by 0.1 mg/kg haloperidol only in core region of neonatal lesioned rats. Apomorphine-induced excitation of neuronal activity (in 21% of all neurons) was reversed by the D1 receptor antagonist SCH23390 (0.1 mg/kg) in all excited neurons. These data support the hypothesis that neonatal but not adult lesions of mPFC alter cortico-striatal networks and suggest that disturbance of mPFC development leads to neurodevelopmental changes in mesoaccumbal DA system during adulthood.

Altered discharge pattern of basal ganglia output neurons in an animal model of idiopathic dystonia.

A decreased activity of basal ganglia output neurons is thought to underlie idiopathic dystonias and other hyperkinetic movement disorders. We found recently a reduced spontaneous discharge rate of entopeduncular neurons (internal globus pallidus in primates) in dt(sz) hamsters, an unique model for idiopathic paroxysmal dystonia in which stress-inducible attacks show an age-dependent severity. Otherwise, it has been suggested that an altered discharge pattern may be more important for the occurrence of dystonia than a reduced discharge rate. Based on qualitative and computerized quantitative evaluations of interspike interval histograms and spike trains of extracellularly recorded single neurons, we investigated the spontaneous discharge pattern of GABAergic entopeduncular and nigral neurons in dt(sz) hamsters at different ages. The discharge pattern of entopeduncular neurons was highly irregular and showed an altered burst-like firing in dt(sz) hamsters at the age of the most marked expression of dystonia when compared with age-matched nondystonic controls. In line with a recently reported normalization of discharge rates after age-dependent disappearance of dystonia, we found an almost complete normalization of the discharge pattern of entopeduncular neurons after remission of dystonia in dt(sz) hamsters. Investigations of GABAergic nigral neurons, reported recently to have the same spontaneous discharge rates in dystonic and nondystonic hamsters, did not show an altered firing pattern in dt(sz) hamsters. The present data clearly indicate the fundamental importance of an altered discharge pattern of entopeduncular neurons for the expression of paroxysmal dystonia, and probably also for other dyskinesias, and may explain the improvements obtained by pallidotomy in dystonic patients despite an obviously reduced pallidal output.