Central fast synaptic transmission is regulated by multiple types of Ca²⁺ channels including N-, P/Q-, R- and other unknown types (Takahashi and Momiyama, 1993; Wheeler et al., 1994). Using selective blockers, previous studied have estimated that the coefficient for the functional relationship between presynaptic Ca²⁺ concentration and transmitter release is 3 or 4 (Dodge and Rahamimoff, 1967; Augustine and Charlton, 1986; Takahashi, 1992; Takahashi and Momiyama, 1993; Momiyama and Koga, 2001). On the other hand, a recent study has found that, in the GABAergic synaptic transmission onto BF cholinergic neurons, unlike the previous studies (Dodge and Rahamimoff, 1967; Augustine and Charlton, 1986; Takahashi, 1992; Takahashi and Momiyama, 1993; Momiyama and Koga, 2001), the relation between extracellular calcium concentration and transmitter release follows a power of less than 2 instead of 3–4 (Nishijo and Momiyama, 2016), suggesting variable transmission mechanisms, including release probability, number of release sites and localization of each subtype of Ca²⁺ channels in relation to release sites, among central synapses.

In the rat striatum, GABAergic synaptic transmission onto cholinergic interneurons is inhibited by activation of presynaptic D2-like DA receptors on the GABAergic terminals (Pisani et al., 2000; Momiyama and Koga, 2001). The inhibitory effects induced by agonist activation of D2-like receptors are occluded after blocking N-type Ca²⁺ channels by ω-conotoxin (ω-CgTX), whereas the inhibition remained unaffected after blocking P/Q-type Ca²⁺ channels by ω-Aga-IV-A (Momiyama and Koga, 2001), suggesting that activation of presynaptic D2-like receptors selectively blocks N-type Ca²⁺ channels, thereby inhibiting GABA release (Figure 1A). The selective coupling is interesting, since the involvement of N-type Ca²⁺ channels is less than that of P/Q-type Ca²⁺ channels in this synapse (Momiyama and Koga, 2001). Among cloned D1–D5 DA receptors, D2-like receptors contains D2, D3 and D4 subtypes. The findings using DA receptor knock-out mice confirmed the involvement of D2 subtype in the D2-like receptor mediated inhibition of GABAergic transmission and selective coupling between D2-like receptors and N-type Ca²⁺ channels (Sato et al., 2014; Yamada et al., 2016).

In the BF, glutamatergic transmission onto cholinergic neurons is inhibited by activation of presynaptic D1-like DA receptors (Momiyama and Fukazawa, 2007). Unlike the case of D2-like receptor-mediated presynaptic inhibition of GABA release in the striatum mentioned above, D1-like receptor-mediated inhibition is occluded after blocking P/Q-type Ca²⁺ channels by ω-Aga-IV-A, whereas the inhibition remained unaffected after blocking N-type Ca²⁺ channels by ω-CgTX (Momiyama and Fukazawa, 2007), suggesting selective coupling between D1-like DA receptors and P/Q-type Ca²⁺ channels in the modulation of glutamate release onto cholinergic neurons in the BF (Figure 1B).

The contribution of N-type Ca²⁺ channels declines with development and almost diminishes within postnatal 2 weeks in the Calyx of Held (Iwasaki and Takahashi, 1998), whereas the contribution remained unchanged in the spinal cord (Iwasaki et al., 2000). In the striatum of rats or mice, the postnatal developmental change undergoes an intermediate pattern; in the GABAergic transmission onto striatal cholinergic interneurons, N-type Ca²⁺ channel contribution gradually decline until postnatal 60 days (Momiyama, 2003). In addition, D2-like DA receptor-mediated presynaptic inhibition decreases with age in parallel with the decline in the contribution of N-type Ca²⁺ channels to the synaptic transmission (Momiyama, 2003; Sato et al., 2014; Yamada et al., 2016; Figures 2A,C).

In the BF glutamatergic transmission onto cholinergic neurons of the rat, selective coupling between D1-like receptors and P/Q-type Ca²⁺ channels mentioned above (Momiyama and Fukazawa, 2007) remains with postnatal development. However, in this glutamatergic synapse, both D1-like receptor-mediated presynaptic inhibition of glutamate release and contribution of P/Q-type Ca²⁺ channels to the synaptic transmission increase in parallel (Momiyama, 2010; Figure 2B), while D2-like receptor-mediated presynaptic inhibition and the N-type Ca²⁺ channels contribution to the synaptic transmission both decrease in the striatum during development (Momiyama, 2003; Sato et al., 2014; Figures 2A,C).

A recent study has demonstrated that GABAergic synaptic transmission onto cholinergic neurons in the BF is inhibited by activation of presynaptic 5-HT_1B receptors, and that the inhibition remained unchanged after blocking N-, P/Q-, or R-type Ca²⁺ channels by selective blockers of each Ca²⁺ channel subtype (Nishijo and Momiyama, 2016). Although the modulation might be regulated by other unknown types of Ca²⁺ channels, the finding could suggest that 5-HT_1B receptor mediated presynaptic inhibition of GABA release is independent of Ca²⁺ channels and/or Ca²⁺ influx to presynaptic terminals. In addition, 5-HT_1B receptor-mediated inhibition was blocked in the presence of 4-AP, a potassium channel blocker, suggesting the involvement of potassium channel modulation in the inhibition of GABA release (Figure 1B). It remains unknown whether Ca²⁺-dependent and Ca²⁺-independent modulation of transmitter release play different roles in these neuronal circuits.

Postnatal days 60 is the age between adolescence and young adult in the rat (Kokoshka et al., 2000). Therefore, the developmental change in the contribution of N-type Ca²⁺ channels to striatal synaptic transmission could be involved in the control of vivid motion or complex behaviors prominent especially in younger ages. These findings also indicate that pharmacological manipulation of N-type Ca²⁺ channels could be at least one of the therapeutic tools for the age-dependent treatment of basal ganglia-related diseases.

On the other hand, BF cholinergic system has been implicated in attention, motivation or memory (Arendt et al., 1989; Dunnett and Fibiger, 1993; Muir et al., 1994) as well as in the related disorders such as Alzheimer’s disease (Price et al., 1986; Mann, 1988; Perry et al., 1993; Gaula and Mesulam, 1994). Therefore, the findings regarding the selective coupling between D1-like receptors and P/Q-type Ca²⁺ channels in the modulation of BF glutamatergic transmission suggest possible involvement of P/Q-type Ca²⁺ channels in these neuropsychiatric functions. Furthermore, a recent finding regarding the involvement of potassium channel modulation in the inhibition of GABA release (Nishijo and Momiyama, 2016) suggests some supplementary role of potassium channels in these functions as well as in the related disorders.

In above-mentioned patch-clamp studies using brain slice preparations of rats or mice, the precise origins of GABAergic or glutamatergic synaptic inputs to striatal or BF neurons are unidentified. The limitations have been overcome with recent advance in optogenetic technique, where certain populations of neurons can be activated by optical stimulation of channelrhodopsin-2 expressed in the neurons. Actually, major origins of GABAergic synaptic inputs onto striatal cholinergic interneurons have been identified to be medium spiny neurons within the striatum (Chuhma et al., 2011). Also, functional synaptic inputs from BF cholinergic neurons to basolateral amygdala neurons have been shown (Unal et al., 2015). Using this technique, input-specific modulation of synaptic transmission as well as selective coupling between receptors and channels will be clarified.

It has been shown that P/Q-type Ca²⁺ channels are expressed on the axon terminal of parvalbumin (PV)-containing interneurons in the cortex (Castejon et al., 2016). PV-containing GABAergic neurons are also one of the main neuronal populations in the BF, sending GABAergic inputs to cholinergic neurons (Duque et al., 2000; Zaborszky and Duque, 2000). Therefore, PV-containing GABAergic neurons in the BF might also express a certain subtypes of Ca²⁺ channels, regulating GABA release onto cholinergic neurons. The issues will be also clarified by future studies using optogenetics in combination with ultrastructural technique.