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Dopamine (DA) modulates glutamate neurotransmission in the striatum. Abnormal DA modulation has been implicated in neurological and psychiatric disorders. The development of DA transporter knock-down (DAT-KD) mice has permitted modeling of these disorders and has shed new light on DA modulation. DAT-KD mice exhibit increased extracellular DA, hyperactivity, and alterations in habituation. We used whole cell patch-clamp recordings from visually identified striatal neurons in slices to examine the effects of DAT-KD on corticostriatal transmission. Electrophysiological recordings from medium-sized spiny neurons in the dorsal striatum revealed alterations in both amplitude and frequency, of spontaneous glutamate receptor-mediated synaptic currents in cells from DAT-KD mice. Furthermore, kinetic analyses revealed that these currents had shorter half-amplitude durations and faster decay times. In contrast, GABA-receptor–mediated synaptic currents were not altered. Striatal neurons from DAT-KD mice also responded differently to amphetamine, cocaine, and DA D2-receptor agonists or antagonists compared with wildtype (WT) littermate controls. In WTs amphetamine and cocaine reduced the frequency of spontaneous glutamate currents and these effects appeared to be mediated by activation of D2 receptors. In contrast, in DAT-KD mice either no changes or only small increases in frequency occurred. D2-receptor agonists or antagonists also had opposing effects in WT and DAT-KD mice. Together, these results indicate that chronically increased extracellular DA produces long-lasting changes in corticostriatal communication that may be mediated by changes in D2-receptor function. These findings have implications for understanding mechanisms underlying attention deficit hyperactivity disorder and Tourette's syndrome and may provide insights into novel therapeutic approaches.

The functional and biophysical properties of a persistent sodium current ( INaP) previously proposed to participate in the generation of subthreshold oscillations and burst discharge in mesencephalic trigeminal sensory neurons (Mes V) were investigated in brain stem slices (rats, p7–p12) using whole cell patch-clamp methods. INaPactivated around −76 mV and peaked at −48 mV, with V1/2of −58.7 mV. Ramp voltage-clamp protocols showed that INaPundergoes time- as well as voltage-dependent inactivation and recovery from inactivation in the range of several seconds (τonset= 2.04 s, τrecov= 2.21 s). Riluzole (≤5 μM) substantially reduced INaP, membrane resonance, postinhibitory rebound (PIR), and subthreshold oscillations, and completely blocked bursting, but produced modest effects on the fast transient Na+current ( INaT). Before complete cessation, burst cycle duration was increased substantially, while modest and inconsistent changes in burst duration were observed. The properties of the INaTwere obtained and revealed that the amplitude and voltage dependence of the resulting “window current” were not consistent with those of the observed INaPrecorded in the same neurons. This suggests an additional mechanism for the origin of INaP. A neuronal model was constructed using Hodgkin-Huxley parameters obtained experimentally for Na+and K+currents that simulated the experimentally observed membrane resonance, subthreshold oscillations, bursting, and PIR. Alterations in the model gNaPparameters indicate that INaPis critical for control of subthreshold and suprathreshold Mes V neuron membrane excitability and burst generation.

The present study was performed to assess the postnatal development and functional roles of inward rectifying currents in rat mesencephalic trigeminal (Mes V) neurons, which are involved in the genesis and control of oral-motor activities. Whole cell voltage-clamp recordings obtained from Mes V neurons in brain stem slices identified fast ( I KIR) and slow ( I h) inward rectifying currents, which were specifically blocked by BaCl2 (300–500 μM) or 4-( N-ethyl- N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride (ZD 7288, 10 μM), respectively. The whole cell current density for these channels increased between postnatal days 2 to 12 (P2-P12), and the time courses for I h activation and deactivation were each well described by two time constants. Application of ZD 7288 produced membrane hyperpolarization in the majority of cells and prolonged afterhyperpolarization repolarization. Additionally, in the presence of ZD 7288, spike frequency was decreased and adaptation was more pronounced. Interestingly, these neurons exhibited a voltage-dependent membrane resonance (hcontributes to stabilizing resting membrane potential and controlling cell excitability. The presence of I himparts the neuron with the unique property of low-frequency membrane resonance; the ability to discriminate between synaptic inputs based on frequency content.

The development of N-methyl-d-aspartate (NMDA)-induced burst discharge in rat trigeminal motoneurons (TMNs) between postnatal days P1 and P10 was examined using whole cell patch-clamp recording methods in brain slices. Bath application of NMDA (50 μM) induced a Mg2+-dependent rhythmical bursting activity starting around P8. Prior to the onset of bursting, the membrane potential depolarized and the input resistance increased. Hyperpolarization of the membrane potential with extrinsic current demonstrated a narrow window of membrane potential where maintained rhythmical burst discharge was evident. In P1–P4 neurons, NMDA application produced membrane depolarization and a minimal change in input resistance, but no burst activity at any membrane potential. Voltage-clamp analysis indicated that the bursting activity was related to the presence or absence of a voltage-dependent Mg2+ block and induction of a negative slope conductance (NSC) region in the I NMDA- V relationship. Regardless of age, reduction of extracellular Mg2+ from 1 mM to 30 μM enhanced I NMDA at voltages negative to −60 mV. However, in 1 mM Mg2+, P1–P4 neurons were devoid of a prominent NSC region compared with P8–P10 neurons, suggesting that the efficacy of depolarization in unblocking the NMDA receptors increased with age. NMDA bursting was not dependent on calcium influx through voltage-gated calcium channels (VGCC) but did require a minimal concentration of Ca2+ in the bath. Intracellular bis-( o-aminophenoxy)- N,N,N′,N′-tetraacetic acid application suppressed burst discharge completely, suggesting that intracellular Ca2+ directly, or via second-messenger systems, regulates NMDA receptor activity and bursting. Interestingly, NMDA bursting could be induced in P1–P4 neurons by simultaneous bath application of serotonin (5-HT, 10 μM), which by itself did not produce bursting, suggesting an “enabling” role for 5-HT. Voltage-clamp analysis demonstrated that the NMDA/5-HT bursting resulted from induction of an NSC in the I-Vrelationship of total membrane current. 5-HT by itself produced no such effect. The mechanisms for this effect were due to an enhancement of the NSC region of the I NMDA- V relationship and reduction of a presumed leak current by 5-HT. These data indicate that NMDA bursting in trigeminal motoneurons is developmentally regulated and subject to neuromessenger modulation. Control of the Mg2+ sensitivity of the NMDA receptor and voltage-dependent block by neuromessengers could be an effective means to control the efficacy of glutamatergic synaptic drive to motoneurons during rhythmical oral-motor activity at early postnatal ages.