Differential expression of long-term potentiation among identified inhibitory inputs to dopamine neurons

Abstract

The in vivo firing pattern of ventral tegmental area (VTA) dopamine neurons is controlled by GABA afferents originating primarily from the nucleus accumbens (NAc), rostromedial tegmental nucleus (RMTg), and local GABA neurons within the VTA. Although different forms of plasticity have been observed from GABA inputs to VTA dopamine neurons, one dependent on cyclic GMP synthesis and the other on adenylyl cyclase activation, it is unknown whether plasticity is differentially expressed in each. Using an optogenetic strategy, we show that identified inhibitory postsynaptic currents (IPSCs) from local VTA GABA neurons and NAc afferents exhibit a cyclic GMP-dependent long-term potentiation (LTP) that is capable of inhibiting the firing activity of dopamine neurons. However, this form of LTP was not induced from RMTg afferents. Only an adenylyl cyclase-mediated increase in IPSCs was exhibited by all three inputs. Thus discrete plasticity mechanisms recruit overlapping but different subsets of GABA inputs to VTA dopamine neurons. We describe a mapping of plasticity expression, mediated by different mechanisms, among three distinct GABA afferents to ventral tegmental area (VTA) dopamine neurons: the rostromedial tegmental nucleus, the nucleus accumbens, and the local GABA neurons within the VTA known to synapse on VTA dopamine neurons. This work is the first demonstration that discrete plasticity mechanisms recruit overlapping but different subsets of GABA inputs to VTA dopamine neurons.

Synaptic function and plasticity in identified inhibitory inputs onto VTA dopamine neurons

“…Furthermore, although synapses arising from VTA GABA neurons did exhibit reliable LTP, it was of smaller magnitude than in our previous studies utilizing electrical stimulation (Nugent et al , 2007, 2009; Niehaus et al , 2010; Graziane et al , 2013; Polter et al , 2014, 2017). Notably, our data are consistent with a recent report using a similar approach, both with respect to the circuit specificity and magnitude of LTP GABA (Simmons et al , 2017). These authors also reported that optically activated nucleus accumbens GABAergic inputs exhibit LTP GABA as well (Simmons et al , 2017).…”

“…Dopamine neurons are relatively depolarized basally and are spontaneously active both in vivo and in brain slices. GABA A R synapses interrupt dopaminergic cell firing both by hyperpolarization and by increasing conductance (Paladini et al , 1999a; Paladini et al , 1999b; Tan et al , 2012; Van Zessen et al , 2012), reducing the firing rate of dopamine neurons as shown in both pharmacological (Johnson & North, 1992; Suaud-Chagny et al , 1992; Paladini et al , 1999b) and optogenetic studies (Tan et al, 2012; Van Zessen et al, 2012; Simmons et al, 2017). Inhibitory synapses in the VTA are also dynamically regulated by experience.…”

“…Local VTA GABAergic neurons comprise approximately 35% of cells in the VTA (Nair-Roberts et al , 2008; Taylor et al , 2014) and form inhibitory synapses onto VTA dopaminergic neurons (Omelchenko and Sesack, 2009a; Tan et al, 2012; Van Zessen et al, 2012; Matsui et al, 2014; Simmons et al, 2017). However, dopamine neurons also receive long-range inhibitory inputs from the rostromedial tegmental nucleus (RMTg, also known as the tail of the VTA; Jhou et al, 2009a; Matsui and Williams, 2011; Lammel et al, 2012; Lecca et al, 2012; Stamatakis and Stuber, 2012; Matsui et al, 2014; Kaufling and Aston-Jones, 2015; Simmons et al, 2017), the ventral pallidum (Haber et al , 1985; Hjelmstad et al , 2013), the bed nucleus of the stria terminalis (BNST) (Jennings et al , 2013), and the nucleus accumbens (Xia et al, 2011; Bocklisch et al, 2013; Edwards et al, 2017; Simmons et al, 2017), as well as from more caudal brain regions (Omelchenko & Sesack, 2010; Sharpe et al , 2017). Inhibitory synapses arising from each of these brain regions are likely to have distinct functional circuit roles and to be differentially regulated by experience.…”

Synaptic plasticity mechanisms common to learning and alcohol use disorder

“…Theta frequency stimulation induces selective LTP of GABA A receptor-mediated synaptic responses that involves activation of GABA B and glutamate type I/II metabotropic receptors in hippocampus (Patenaude et al 2003). GABA neurons in the ventral tegmental area (VTA) and accumbal GABAergic afferents also exhibit LTP after high frequency stimulation (Nugent et al 2007;Simmons et al 2017). However, much less is known about GABAergic LTP.…”

Could GABA, with a side of glycine, control glutamate receptors?

“…() isolate and differentiate two of the major sources of inhibition arriving at dopamine neurons: The GABA‐releasing terminals from local GABA interneurons within the VTA, and from a region at the caudal tail of the VTA, termed the rostromedial tegmental nucleus (RMTg). The authors demonstrate that local VTA‐ and RMTg‐originating terminals define distinct channels of inhibition that possess unique spatial distributions, synaptic properties and capacities for long‐ and short‐term plasticity (see also Simmons et al ., ). Most intriguingly, the authors report two key properties of RMTg GABA‐releasing terminals: (i) They fail to express a unique form of long‐term potentiation previously characterized at VTA GABAergic terminals (i.e., LTP GABA ); and (ii) they corelease the neurotransmitter glycine.…”