SUMMARY Salient stimuli redirect attention and suppress ongoing motor activity. This attentional shift is thought to rely upon thalamic signals to the striatum to shift cortically driven action selection, but the network mechanisms underlying this interaction are unclear. Using a brain slice preparation that preserved cortico- and thalamostriatal connectivity, it was found that activation of thalamostriatal axons in a way that mimicked the response to salient stimuli induced a burst of spikes in striatal cholinergic interneurons that was followed by a pause lasting more than half a second. This patterned interneuron activity triggered a transient, presynaptic suppression of cortical input to both major classes of principal medium spiny neuron (MSN), that gave way to a prolonged enhancement of postsynaptic responsiveness in striatopallidal MSNs controlling motor suppression. This differential regulation of the corticostriatal circuitry provides a neural substrate for attentional shifts and cessation of ongoing motor activity with the appearance of salient environmental stimuli.

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. The effects were sex-specific, i.e., the reduction of Ba2+ currents was greater in neurons taken from female rats. 17 beta-Estradiol primarily targeted L-type currents, and their inhibition was detected reliably within seconds of administration. The maximum reduction by 17 beta-estradiol occurred at picomolar concentrations. 17 beta-Estradiol conjugated to bovine serum albumin also reduced Ba2+ currents, suggesting that the effect occurs at the membrane surface. Dialysis with GTP gamma S prevented reversal of the modulation, suggesting that 17 beta-estradiol acts via G-protein activation. 17 alpha-Estradiol also reduced Ba2+ currents but was significantly less effective than 17 beta-estradiol. Estriol and 4-hydroxyestradiol were found to reduce Ba2+ currents with similar efficacy to 17 beta-estradiol, whereas estrone and 2-methoxyestriol were less effective. Tamoxifen also reduced Ba2+ currents but did not occlude the effect of 17 beta-estradiol. These results suggest that at physiological concentrations, 17 beta-estradiol can have immediate actions on neostriatal neurons via nongenomic signaling pathways.

Most in vitro studies of D 1 dopaminergic modulation of excitability in neostriatal medium spiny neurons have revealed inhibitory effects. Yet studies made in more intact preparations have shown that D 1 receptors can enhance or inhibit the responses to excitatory stimuli. One explanation for these differences is that the effects of D 1 receptors on excitability are dependent on changes in the membrane potential occurring in response to cortical inputs that are seen only in intact preparations. To test this hypothesis, we obtained voltage recordings from medium spiny neurons in slices and examined the impact of D 1 receptor stimulation at depolarized and hyperpolarized membrane potentials. As previously reported, evoked discharge was inhibited by D 1 agonists when holding at negative membrane potentials (approximately Ϫ80 mV ). However, at more depolarized potentials (approximately Ϫ55 mV ), D 1 agonists enhanced evoked activity. At these potentials, D 1 agonists or cAMP analogs prolonged or induced slow subthreshold depolarizations and increased the duration of barium-or TEAinduced Ca 2ϩ -dependent action potentials. Both effects were blocked by L-type Ca 2ϩ channel antagonists (nicardipine, calciseptine) and were occluded by the L-type channel agonist BayK 8644 -arguing that the D 1 receptor-mediated effects on evoked activity at depolarized membrane potential were mediated by enhancement of L-type Ca 2ϩ currents. These results reconcile previous in vitro and in vivo studies by showing that D 1 dopamine receptor activation can either inhibit or enhance evoked activity, depending on the level of membrane depolarization.

Unlike other neostriatal neurons, cholinergic interneurons exhibit spontaneous, low-frequency, repetitive firing. To gain an understanding of the K+ channels regulating this behavior, acutely isolated adult rat cholinergic interneurons were studied using whole-cell voltage-clamp and single-cell reverse transcription-PCR techniques. Cholinergic interneurons were identified by the presence of choline acetyltransferase (ChAT) mRNA. Depolarization-activated potassium currents in cholinergic interneurons were dominated by a rapidly inactivating, K+-selective A current that became active at subthreshold potentials. Depolarizing prepulses inactivated this component of the current, leaving a delayed, rectifier-like current. Micromolar concentrations of Cd2+ dramatically shifted the voltage dependence of the A current without significantly affecting the delayed rectifier. The A-channel antagonist 4-aminopyridine (4-AP) produced a voltage-dependent block (IC50, approximately 1 mM) with a prominent crossover at millimolar concentrations. On the other hand, TEA preferentially blocked the sustained current component at concentrations <10 mM. Single-cell mRNA profiling of subunits known to give rise to rapidly inactivating K+ currents revealed the coexpression of Kv4.1, Kv4.2, and Kv1.4 mRNAs but low or undetectable levels of Kv4.3 and Kv3.4 mRNAs. Kv1.1, beta1, and beta2 subunit mRNAs, but not beta3, were also commonly detected. The inactivation recovery kinetics of the A-type current were found to match those of Kv4.2 and 4.1 channels and not those of Kv1.4 or Kv1. 1 and beta1 channels. Immunocytochemical analysis confirmed the presence of Kv4.2 but not Kv1.4 subunits in the somatodendritic membrane of ChAT-immunoreactive neurons. These results argue that the depolarization-activated somatodendritic K+ currents in cholinergic interneurons are dominated by Kv4.2- and Kv4. 1-containing channels. The properties of these channels are consistent with their playing a prominent role in governing the slow, repetitive discharge of interneurons seen in vivo.

In recent years, the distribution of dopamine receptor subtypes among the principal neurons of the neostriatum has been the subject of debate. Conventional anatomical and physiological approaches have yielded starkly different estimates of the extent to which D 1 and D 2 class dopamine receptors are colocalized. One plausible explanation for the discrepancy is that some dopamine receptors are present in physiologically significant numbers, but the mRNA for these receptors is not detectable with conventional techniques. To test this hypothesis, we examined the expression of DA receptors in individual neostriatal neurons by patch-clamp and RT-PCR techniques. Because of the strong correlation between peptide expression and projection site, medium spiny neurons were divided into three groups on the basis of expression of mRNA for enkephalin (ENK) and substance P (SP The signaling pathways activated by dopamine in the neostriatum have been the subject of intense study since it was discovered that the loss of dopamine leads to the psychomotor symptoms of Parkinson's disease (Hornykiewcz, 1973). Subsequently, several other common psychomotor disorders, including schizophrenia and Tourette's syndrome, have been linked to alterations in neostriatal dopaminergic signaling (Nemeroff and Bissette, 1988;Erenberg, 1992). In recent years, significant progress has been made in characterizing the membrane receptors transducing the signals of dopamine in the neostriatum and the brain in general. How these receptors are distributed among the principal neuronal cell types in the neostriatum has been the subject of debate (Surmeier et al., 1993). This controversy stems primarily from discrepancies in the results obtained from functional studies on the one hand and anatomical studies on the other. The most compelling anatomical data are in situ hybridization studies suggesting that D 1a and D 2 mRNA are segregated primarily in the two major efferent neostriatal populations (Gerfen, 1992; LeMoine and Bloch, 1995). In particular, D 1a receptor mRNA is found in substance P-expressing (SP) neurons projecting to the substantia nigra, whereas D 2 receptor mRNA is found in enkephalin-expressing (ENK) neurons projecting exclusively to the globus pallidus. More recent immunocytochemical work supports this conclusion (Hersch et al., 1995), although others have reported significant degrees of receptor protein colocalization .Functional studies, on the other hand, repeatedly have observed responses to D 1 and D 2 class agonists that are difficult to explain if these receptor classes are not colocalized (Uchimura et al., 1986;Akaike et al., 1987;Cepeda et al., 1993; for review, see Surmeier et al., 1993). The most compelling evidence comes from patch-clamp studies of acutely isolated neostriatal neuronswhere synaptic interactions have been removed-showing neuromodulatory effects of both D 1 and D 2 class agonists in the same cell (Surmeier et al., 1992). In this study, it was also shown that neurons projecting axons to the substantia nigra coexp...