The weaver mutation of GIRK2 results in a loss of inwardly rectifying K+ current in cerebellar granule cells.

The weaver mutation in mice results in a severe ataxia that is attributable to the degeneration of cerebellar granule cells and dopaminergic neurons in the substantia nigra. Recent genetic studies indicate that the GIRK2 gene is altered in weaver. This gene codes for a G-protein-activated, inwardly rectifying K+ channel protein (8).

Isolation and characterization of a persistent potassium current in neostriatal neurons.

1. Depolarization-activated, calcium-independent potassium (K+) currents were studied with the use of whole cell voltage-clamp recording from neostriatal neurons acutely isolated from adult (> or = 4 wk old) rats. The whole cell K+ current was composed of transient and persistent components.

Multiplicity of glutamate receptor subunits in single striatal neurons: an RNA amplification study.

The RNA amplification technique was used to examine the pattern of coexpression of mRNAs encoding 16 subtypes/subunits of the glutamate receptor (GluR) in acutely dissociated neurons from adult rat striata. THe signal intensity for each mRNA varied within single neurons, but the general pattern of low versus high expression signals was similar among neurons, except for the GluR4 subunit of the (+/-)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. The mRNAs for GluR1-3 subunits of the AMPA receptor were present in all cells, with the signal intensity of GluR1 mRNAs usually the lowest.

Muscarinic (m2/m4) receptors reduce N- and P-type Ca2+ currents in rat neostriatal cholinergic interneurons through a fast, membrane-delimited, G-protein pathway.

The signaling pathways mediating the muscarinic modulation of Ca2+ currents in neostriatal cholinergic interneurons were studied by combined patch-clamp recording and single-cell reverse transcription-PCR. Cholinergic interneurons were identified by the presence of choline acetyltransferase mRNA. These neurons expressed Q-, N-, L-, P-, and R-type Ca2+ currents and the mRNA for the alpha1 subunits believed to form the channels underlying these currents (classes A, B, C, D, and E).

Estradiol reduces calcium currents in rat neostriatal neurons via a membrane receptor.

Until recently, steroid hormones were believed to act only on cells containing intracellular receptors. However, recent evidence suggests that steroids have specific and rapid effects at the cellular membrane. Using whole-cell patch-clamp techniques, 17 beta-estradiol was found to reduce Ba2+ entry reversibly via Ca2+ channels in acutely dissociated and cultured neostriatal neurons.

Glutamate-mediated excitotoxic death of cultured striatal neurons is mediated by non-NMDA receptors.

Considerable interest has focused on the role of glutamate-mediated excitotoxicity in neurodegenerative disorders of the basal ganglia. The in vitro data on the receptor mechanisms involved in this process, however, have been inconclusive. Some studies have indicated that excitotoxins acting at NMDA receptors kill striatal neurons and others have indicated that NMDA receptor-mediated excitotoxic death of striatal neurons is minimal in the absence of cortex.

Modulation of calcium currents by a D1 dopaminergic protein kinase/phosphatase cascade in rat neostriatal neurons.

In rat neostriatal neurons, D1 dopamine receptors regulate the activity of cyclic AMP-dependent protein kinase (PKA) and protein phosphatase 1 (PP1). The influence of these signaling elements on high voltage-activated (HVA) calcium currents was studied using whole-cell voltage-clamp techniques. The application of D1 agonists or cyclic AMP analogs reversibly reduced N- and P-type Ca2+ currents.

Muscarinic receptors modulate N-, P-, and L-type Ca2+ currents in rat striatal neurons through parallel pathways.

Muscarinic modulation of calcium currents was studied in acutely isolated striatal neurons from the adult rat using the whole-cell configuration of the patch-clamp technique. Muscarinic agonists reduced calcium currents through two distinct signaling pathways. One pathway depended upon PTX-sensitive G-proteins and targeted N- and P-type currents.

Dopaminergic regulation of striatal efferent pathways.

In the past year there has been a growing debate about the distribution of dopamine receptors in striatal efferent pathways. As is often the case, different approaches lead to different perspectives. Nevertheless, the available data can be reconciled with a model in which D1 and D2 dopamine receptors are segregated in the distal dendrites and axonal terminal fields of striatonigral and striatopallidal neurons, but intermingled in the soma and proximal dendrites.

Cellular and molecular characterization of Ca2+ currents in acutely isolated, adult rat neostriatal neurons.

Ca2+ currents in acutely isolated, adult rat neostriatal neurons were studied with whole-cell voltage-clamp techniques. In the vast majority of neurons (approximately 90%, n > 250), currents were exclusively of the high-voltage-activated (HVA) type. HVA currents activated near -40 mV and reached their maximum amplitude near 0 mV.

Opioids decrease high-voltage activated calcium currents in acutely dissociated neostriatal neurons.

Although the distribution of opioid receptors is central to the patch-matrix model of neostriatal organization, it has been unclear whether these receptors are located post-synaptically. Moreover, it has not yet been clarified whether opioid receptor activation in neostriatum results in the modulation of calcium and/or potassium conductances. To test this, neostriatal neurons were acutely isolated and their sensitivity to opioid receptor agonists determined.

Acutely isolated neurons of the rat globus pallidus exhibit four types of high-voltage-activated Ca2+ current.

1. Large, projection-like neurons from the adult (> 3 wk post-natal) rat globus pallidus (GP) were acutely isolated and subjected to whole-cell voltage-clamp (n = 37). Ca2+ currents were isolated pharmacologically in cells with whole-cell capacitances of 15-34 pF.

Somatostatin- and substance P-like immunoreactivity in rat neostriatal cultures.

In the normal adult neostriatum, somatostatin immunoreactive interneurons constitute a few percent of the total neuronal population whereas substance P immunoreactive neurons, which project to the substantia nigra, constitute nearly half of the total. Primary monolayer neostriatal cultures derived from E17 rat brains displayed both somatostatin-like and substance P-like immunoreactivity (SOM-IR and SP-IR). However, the proportions of SOM-IR and SP-IR neurons in vitro were significantly different from those in vivo.

Are neostriatal dopamine receptors co-localized?

The postsynaptic effects of dopamine in the neostriatum are mediated by five G-protein-coupled receptors. The extent to which these receptors are co-localized in neostriatal neurons has become controversial. This debate has far-reaching implications for treatment strategies in disorders of dopaminergic signaling, such as Parkinson's disease and schizophrenia.

Voltage-gated potassium currents in acutely dissociated rat cortical neurons.

1. We describe three outward K+ current components in acutely dissociated neurons from rat sensorimotor cortex on the basis of inactivation kinetics and voltage dependence. 2.

Cholinergic and dopaminergic modulation of potassium conductances in neostriatal neurons.

Muscarinic and dopaminergic ligands exert their principal effects on excitability by modulating voltage-dependent conductances. Potassium currents activated by depolarization are among the conductances modulated. These currents can be divided into rapidly (Af) and slowly inactivating (A(s)) A-currents and a delayed rectifier current.

D1 and D2 dopamine receptor modulation of sodium and potassium currents in rat neostriatal neurons.

The potassium and sodium currents in acutely isolated neostriatal neurons are modulated by activation of both D1- and D2-class receptors. The amplification of mRNA in individual neurons supports this conclusion and has shown that striatonigral neurons express not only D1 and D2 receptors, but D3 receptors as well. The characteristics of the modulations produced by these receptors provide a foundation for both antagonistic and synergistic actions of D1 and D2 agonists in the neostriatum.

Dopamine receptor subtypes colocalize in rat striatonigral neurons.

Dopaminergic neurons of the substantia nigra provide one of the major neuromodulatory inputs to the neostriatum. Recent in situ hybridization experiments have suggested that postsynaptic dopamine receptors are segregated in striatonigral and striatopallidal neurons. We have tested this hypothesis in acutely isolated, retrogradely labeled striatonigral neurons by examining the neuromodulatory effects of selective dopaminergic agonists on Na currents and by probing single-cell antisense RNA populations with dopamine receptor cDNAs.

Grafted neostriatal neurons express a late-developing transient potassium current.

Previous anatomical and physiological studies of neostriatal grafts have suggested that transplanted neurons do not develop beyond an early postnatal stage. We have tested whether this hypothesis can be generalized by characterizing the developmentally regulated Ca-independent potassium currents in graft neurons. These currents were studied using a combination of the whole-cell voltage-clamp technique with acutely-dissociated neurons and intracellular recording in slices.

High- and low-voltage activated calcium currents are expressed by neurons cultured from embryonic rat neostriatum.

Current-clamp studies have shown that voltage-dependent Ca currents are present in rat neostriatal neurons. Although these studies have provided evidence for the presence of high-voltage activated Ca channels, it has been unclear whether low-voltage activated channels are also present. Using the whole-cell variant of the patch-clamp technique, we have studied isolated Ca currents in an attempt to answer this question.

Developmental regulation of a slowly-inactivating potassium conductance in rat neostriatal neurons.

In late embryonic and early post-natal rat neostriatal neurons, the voltage-dependent potassium currents activated by depolarization are largely attributable to a rapidly inactivating A-current and a delayed rectifier current. Over the first 4 weeks of post-natal life, a third potassium current emerges in most cells. This slowly inactivating conductance is distinct from the A-current and delayed rectifier in voltage-dependence, kinetics and pharmacology.

Muscarinic regulation of cyclic AMP metabolism in rat neostriatal cultures.

Muscarinic receptor expression and function were investigated in cultured rat neostriatum. Muscarinic receptor levels were determined from saturation binding experiments performed on intact cultures using [3]N-methylscopolamine. In cultures maintained for 3, 7 and 12-14 days in vitro, the Bmax was 2.

Serotonin enhances excitability in neostriatal neurons by reducing voltage-dependent potassium currents.

The physiological effects of serotonin (5-HT) on rat neostriatal neurons were investigated using current-clamp techniques in neostriatal slices and voltage-clamp techniques in acutely dissociated adult neostriatal neurons. In most neurons (35/51), bath-applied 5-HT (10-60 microM) decreased the first spike latency and increased the evoked firing frequency. Membrane input resistance was also increased in most neurons (33/35) but could not explain the enhanced responsiveness.

Quinolinate and kainate neurotoxicity in neostriatal cultures is potentiated by co-culturing with neocortical neurons.

It has been suggested that a disorder in the regulation of excitatory amino acids (EAA) may underlie the loss of neostriatal neurons seen in Huntington's disease. The role of neocortical afferent fibers in determining the EAA sensitivity of neostriatal neurons was assessed by comparing EAA toxicity in co-cultures of neocortex and neostriatum with that of neostriatum alone. In cultures of neostriatum alone, EAAs produced only modest neuronal losses.

Muscarinic modulation of a transient K+ conductance in rat neostriatal neurons.

Neurons of the neostriatum are richly innervated by cholinergic neurons of intrinsic origin. Both pre- and post-synaptic muscarinic receptors mediate the effects of acetylcholine (ACh). Activation of these receptors is functionally significant, particularly in Parkinson's disease.