Sex differences in the effects of early neocortical injury on neuronal size distribution of the medial geniculate nucleus in the rat are mediated by perinatal gonadal steroids. (1/1641)

Freezing injury to the cortical plate of rats induces cerebrocortical microgyria and, in males but not females, a shift toward greater numbers of small neurons in the medial geniculate nucleus (MGN). The purpose of the current study was to examine a hormonal basis for this sex difference. Cross-sectional neuronal areas of the MGN were measured in male rats, untreated female rats and female rats treated perinatally with testosterone propionate, all of which had received either neonatal cortical freezing or sham injury. Both male and androgenized female rats with microgyria had significantly smaller MGN neurons when compared to their sham-operated counterparts, whereas untreated females with microgyria did not. These differences were also reflected in MGN neuronal size distribution: both male and androgenized female rats with microgyria had more small and fewer large neurons in their MGN in comparison to shams, while there was no difference in MGN neuronal size distribution between lesioned and sham females. These findings suggest that perinatal gonadal steroids mediate the sex difference in thalamic response to induction of microgyria in the rat cortex.  (+info)

Developmental synaptic changes increase the range of integrative capabilities of an identified excitatory neocortical connection. (2/1641)

Excitatory synaptic transmission between pyramidal cells and fast-spiking (FS) interneurons of layer V of the motor cortex was investigated in acute slices by using paired recordings at 30 degrees C combined with morphological analysis. The presynaptic and postsynaptic properties at these identified central synapses were compared between 3- and 5-week-old rats. At these two postnatal developmental stages, unitary EPSCs were mediated by the activation of AMPA receptors with fast kinetics at a holding potential of -72 mV. The amplitude distribution analysis of the EPSCs indicates that, at both stages, pyramidal-FS connections consisted of multiple functional release sites. The apparent quantal size obtained by decreasing the external calcium ([Ca2+]e) varied from 11 to 29 pA near resting membrane potential. In young rats, pairs of presynaptic action potentials elicited unitary synaptic responses that displayed paired-pulse depression at all tested frequencies. In older animals, inputs from different pyramidal cells onto the same FS interneuron had different paired-pulse response characteristics and, at most of these connections, a switch from depression to facilitation occurred when decreasing the rate of presynaptic stimulation. The balance between facilitation and depression endows pyramidal-FS connections from 5-week-old animals with wide integrative capabilities and confers unique functional properties to each synapse.  (+info)

Inhibition of transient and persistent Na+ current fractions by the new anticonvulsant topiramate. (3/1641)

The actions of the antiepileptic drug topiramate (TPM) on Na+ currents were assessed using whole-cell patch-clamp recordings in dissociated neocortical neurons and intracellular recordings in neocortical slices. Relatively low TPM concentrations (25-30 microM) slightly inhibited the persistent fraction of Na+ current in dissociated neurons and reduced the Na+-dependent long-lasting action potential shoulders, which can be evoked in layer V pyramidal neurons after Ca++ and K+ current blockade. Conversely, the same drug concentrations were ineffective in reducing the amplitude of the fast Na+-dependent action potentials evoked in slices or the peak of transient Na+ (INaf) current evoked in isolated neurons from a physiological holding potential. Consistent INaf inhibition became, however, evident only when the neuronal membrane was kept depolarized to enhance resting Na+ channel inactivation. TPM (100 microM) was ineffective on the voltage dependence of activation but induced a leftward shift of the steady-state INaf inactivation curve. The drug-induced inhibitory effect increased with the duration of membrane depolarization, and the recovery of INaf after long membrane depolarizations was slightly delayed in comparison with that observed under control conditions. The obtained evidence suggests that the anticonvulsant action of TPM may operate by stabilizing channel inactivation, which can be induced by depolarizing events similar to those occurring in chronic epileptic conditions. Concurrently, the slight but significant inhibition of the persistent fraction of the Na+ current, obtained with the application of relatively low TPM concentrations, may contribute toward its anticonvulsant effectiveness by modulating the near-threshold depolarizing events that are sustained by this small current fraction.  (+info)

Impairment of neocortical long-term potentiation in mice deficient of endothelial nitric oxide synthase. (4/1641)

The role of the possible retrograde messenger nitric oxide (NO) in the induction of long-term potentiation (LTP) was studied in supragranular layers of somatosensory cortical slices obtained from adult mice. High-frequency stimulation produced a slowly rising, long-lasting (50 min) and significant (P < 0.001) increase in the extracellular synaptic response by 23%. The induction of LTP was independent from activation of N-methyl-D-aspartate (NMDA) receptors, but prevented by bath application of NG-nitro-L-arginine methyl ester (L-NAME), indicating that one or several of the different NO synthases (NOS) produced NO within the postsynaptic neuron. No LTP could be induced in knockout mice lacking the endothelial NOS (eNOS) isoform. These data suggest that eNOS is involved in an NMDA receptor-independent form of LTP in the rodent cerebral cortex.  (+info)

Preferential Zn2+ influx through Ca2+-permeable AMPA/kainate channels triggers prolonged mitochondrial superoxide production. (5/1641)

Synaptically released Zn2+ can enter and cause injury to postsynaptic neurons. Microfluorimetric studies using the Zn2+-sensitive probe, Newport green, examined levels of [Zn2+]i attained in cultured cortical neurons on exposure to N-methyl-D-asparte, kainate, or high K+ (to activate voltage-sensitive Ca2+ channels) in the presence of 300 microM Zn2+. Indicating particularly high permeability through Ca2+-permeable alpha-amino3-hydroxy-5-methyl-4-isoxazolepropionic-acid/kainate (Ca-A/K) channels, micromolar [Zn2+]i rises were observed only after kainate exposures and only in neurons expressing these channels [Ca-A/K(+) neurons]. Further studies using the oxidation-sensitive dye, hydroethidine, revealed Zn2+-dependent reactive oxygen species (ROS) generation that paralleled the [Zn2+]i rises, with rapid oxidation observed only in the case of Zn2+ entry through Ca-A/K channels. Indicating a mitochondrial source of this ROS generation, hydroethidine oxidation was inhibited by the mitochondrial electron transport blocker, rotenone. Additional evidence for a direct interaction between Zn2+ and mitochondria was provided by the observation that the Zn2+ entry through Ca-A/K channels triggered rapid mitochondrial depolarization, as assessed by using the potential-sensitive dye tetramethylrhodamine ethylester. Whereas Ca2+ influx through Ca-A/K channels also triggers ROS production, the [Zn2+]i rises and subsequent ROS production are of more prolonged duration.  (+info)

Growth factor-mediated Fyn signaling regulates alpha-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor expression in rodent neocortical neurons. (6/1641)

Src-family protein tyrosine kinases (PTKs) transduce signals to regulate neuronal development and synaptic plasticity. However, the nature of their activators and molecular mechanisms underlying these neural processes are unknown. Here, we show that brain-derived neurotrophic factor (BDNF) and platelet-derived growth factor enhance expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor 1 and 2/3 proteins in rodent neocortical neurons via the Src-family PTK(s). The increase in AMPA receptor levels was blocked in cultured neocortical neurons by addition of a Src-family-selective PTK inhibitor. Accordingly, neocortical cultures from Fyn-knockout mice failed to respond to BDNF whereas those from wild-type mice responded. Moreover, the neocortex of young Fyn mutants exhibited a significant in vivo reduction in these AMPA receptor proteins but not in their mRNA levels. In vitro kinase assay revealed that BDNF can indeed activate the Fyn kinase: It enhanced tyrosine phosphorylation of Fyn as well as that of enolase supplemented exogenously. All of these results suggest that the Src-family kinase Fyn, activated by the growth factors, plays a crucial role in modulating AMPA receptor expression during brain development.  (+info)

Optical imaging of functional domains in the cortex of the awake and behaving monkey. (7/1641)

As demonstrated by anatomical and physiological studies, the cerebral cortex consists of groups of cortical modules, each comprising populations of neurons with similar functional properties. This functional modularity exists in both sensory and association neocortices. However, the role of such cortical modules in perceptual and cognitive behavior is unknown. To aid in the examination of this issue we have applied the high spatial resolution optical imaging methodology to the study of awake, behaving animals. In this paper, we report the optical imaging of orientation domains and blob structures, approximately 100-200 micrometer in size, in visual cortex of the awake and behaving monkey. By overcoming the spatial limitations of other existing imaging methods, optical imaging will permit the study of a wide variety of cortical functions at the columnar level, including motor and cognitive functions traditionally studied with positron-emission tomography or functional MRI techniques.  (+info)

Reduction of calcineurin activity in brain by antisense oligonucleotides leads to persistent phosphorylation of tau protein at Thr181 and Thr231. (8/1641)

Phosphorylation of tau protein promotes stability of the axonal cytoskeleton; aberrant tau phosphorylation is implicated in the biogenesis of paired helical filaments (PHF) seen in Alzheimer's disease. Protein kinases and phosphatases that modulate tau phosphorylation have been identified using in vitro techniques; however, the role of these enzymes in vivo has not been determined. We used intraventricular infusions of antisense oligodeoxynucleotides (ODNs) directed against the major brain isoforms of the Ca2+/calmodulin-dependent phosphatase calcineurin to determine how reduced activity of this enzyme would affect tau dephosphorylation. Five-day infusions of antisense ODNs (5 and 10 nmol/day) in rats decreased immunoreactive levels and activity of calcineurin throughout the brain; sense ODNs, scrambled ODNs, and infusion vehicle alone had no effect. When neocortical slices were prepared from antisense ODN-treated rats and incubated for 1 to 2 h in vitro, tau protein remained phosphorylated as determined by using the phosphorylation-sensitive monoclonal antibodies AT-180 (Thr231) and AT-270 (Thr181). In contrast, AT-180 and AT-270 sites were completely dephosphorylated during incubation of neocortical slices from vehicle-infused controls and sense ODN-treated rats. Neocortical slices from antisense-treated rats were incubated with the phosphatase inhibitors okadaic acid (100 nM; 10 microM) and FK-520 (5 microM); these preparations showed enhanced tau phosphorylation, consistent with a significant loss of calcineurin activity. Thus, we conclude that phosphorylation of at least two sites on tau protein, namely, Thr181 and Thr231, is regulated by calcineurin.  (+info)