Spontaneous Voltage Oscillations in Striatal Projection Neurons in a Rat Corticostriatal Slice

The striatum is a component of the basal ganglia circuitry controlling movement, associative learning and procedural memory (e.g. Beiser & Houk, 1998). Its output neurons are the medium spiny neurons (Wilson, 1993). In vivo, these neurons move between hyperpolarized ‘down-states’ and depolarized ‘up-states’ in response to cortical excitatory synaptic input (Wilson, 1993; Stern et al. 1997). We wanted to know whether similar voltage fluctuations could be induced in vitro. In a variety of cell types, the generation of stable depolarized states depends upon a combination of synaptic inputs and intrinsic conductances (e.g. Lee & Heckman, 1998a;Russo & Hounsgaard, 1999). Persistent or slowly inactivating Ca2+ currents (Seamans et al. 1997; Carlin et al. 2000; Perrier & Hounsgaard, 2000) and slowly inactivating sodium currents (Schwindt & Crill, 1998; Hsiao et al. 1998; Larkum et al. 2001) figure prominently in the maintenance of depolarized plateau potentials in many neurons. These currents create a region of negative slope conductance and a second stable point in the current–voltage relationship (Booth et al. 1997; Kiehn & Eken, 1998; Hsiao et al. 1998; Lee & Heckman, 1998b; Schiller & Schiller, 2001; Svirskis et al. 2001). In this situation, neurons become bistable, allowing transient depolarizing synaptic inputs to produce prolonged depolarizations and sustained periods of spiking. Sustained periods of spiking are the cellular correlate of working memory (Romo et al. 1999; Compte et al. 2000; Egorov et al. 2002) and the neostriatum with prefrontal and motor cortices are posited as the basic circuit for procedural memory (Beiser & Houk, 1998). Often, bistability emerges in response to agonists or neuromodulators that enhance NMDA and inward currents (Guertin & Hounsgaard, 1998; Perrier & Hounsgaard, 2000; Wang & O'Donnell, 2001; Schiller & Schiller, 2001; Egorov et al. 2002). One of these inward currents is carried by L-type Ca2+ channels (Hounsgaard & Kiehn, 1989) and L-type Ca2+ channels are known to be modulated by dopamine in neostriatal neurons (Hernandez-Lopez et al. 1997, 2000). Two types of these channels have been located in the somato-dendritic membrane of many neurons: Cav1.2 and Cav1.3 (Westenbroek et al. 1998; Xu & Lipscombe, 2001). Cav1.3 L-type channels may be particularly important in this regard as they activate at subthreshold membrane potentials (Koschak et al. 2001; Xu & Lipscombe, 2001). Striatal medium spiny neurons express mRNA for both subtypes and have a prominent L-type current at subthreshold membrane potentials (Bargas et al. 1994; Olson et al. 2001). The contribution of this current to shape the normal firing pattern (Galarraga et al. 1989, 1994; Perez-Garci et al. 2003) and the synaptic responses (Galarraga et al. 1997; Akopian & Walsh, 2002) are well-established. Enhancement or block of these currents with dihydropyridine L-type channel agonists and antagonists facilitates or blocks, respectively, plateau potentials or their underlying currents in spiny neurons (Galarraga et al. 1997; Hernandez-Lopez et al. 1997, 2000; Cepeda et al. 1998; Akopian & Walsh, 2002). Therefore, we asked whether synaptic activation could be elicited in conditions that were permissive for the participation of these inward currents. In addition, we wanted to explore whether the participation of these inward currents would favour the generation of spontaneous voltage oscillations. In slices that preserve some measure of corticostriatal connectivity, it was seen that transient stimulation of the cortex is capable of inducing long-lasting plateau potentials in spiny neostriatal neurons (Bargas et al. 1991; Galarraga et al. 1997; Schlosser et al. 1999). Similar plateau potentials have been observed in vivo (Herrling et al. 1983; Wilson et al. 1983). It was also observed that, upon repetitive stimulation, plateau potentials were often followed by spontaneous fluctuations between two different membrane potentials. The probability of these transitions was strongly modulated by the enhancement of inward currents known to underlie bistability in several cell types - namely L-type Ca2+ and NMDA currents.