Actions of GABA at Glutamatergic Synapses in Accumbens
Kevin M. Manz, Andrew G. Baxley, Zack Zurawski, Heidi E. Hamm, and Brad A. Grueter
(see pages 9277–9293)
The nucleus accumbens (NAc) has central roles in reinforcement learning and reward seeking, and thus in the development of substance abuse disorders. Understanding how circuits within the NAc are modified by rewards and are activated by reward-related cues may therefore help to identify targets for addiction therapies. One such target is GABAB receptors (GABABRs). In rodents, the GABABR agonist baclofen decreases conditioned place preference for drugs of abuse and reduces reinstatement of drug seeking after extinction. These effects are mediated partly by GABABR-dependent inhibition of dopamine release in the NAc.
Low-frequency activation of GABAergic interneurons in the NAc (at time indicated by bar) caused a reduction in eEPSC amplitude in control conditions (gray). The effect was blocked by a GABABR antagonist (black circles) and was enhanced by a positive allosteric modulator of GABABRs (blue circles). See Manz et al. for details.
Manz et al. have discovered that baclofen also reduces glutamate release in the NAc. Baclofen decreased the amplitude of evoked EPSCs (eEPSCs) in medium spiny neurons (MSNs) that expressed dopamine D1 receptors (D1Rs), as well as in putative D2R-expressing MSNs. Furthermore, baclofen increased the paired-pulse ratio and coefficient of variation of eEPSCs and decreased the frequency of miniature EPSCs in MSNs, suggesting that it reduced the probability of glutamate release onto these cells.
Blocking GABA reuptake also decreased eEPSC amplitude in MSNs, and this effect was enhanced by a positive allosteric modulator of GABABRs. Notably, light-mediated, low-frequency activation of parvalbumin-expressing, fast-spiking GABAergic interneurons in the NAc decreased eEPSC amplitude in MSNs. In this case, however, the effect was stronger in D1R-expressing than in putative D2R-expressing neurons.
GABABRs are Gi/o-coupled receptors, and in other neuron types their presynaptic effects are mediated at least partly by Gβγ subunits. Specifically, Gβγ subunits reduce release probability by reducing calcium influx through voltage-gated channels and by directly interacting with SNAP-25, a protein that helps mediate vesicle fusion. Manz et al. found that blocking calcium channels did not occlude the effect of baclofen on eEPSCs in MSNs, but increasing calcium influx reduced the effect of baclofen. Furthermore, the effect of baclofen was diminished in MSNs that expressed a mutant form of SNAP-25 that lacked the Gβγ-binding motif.
These results suggest that GABA released from fast-spiking interneurons in the NAc activates GABABRs on glutamatergic inputs to MSNs, and that this reduces the probability of neurotransmitter release by interfering with vesicle release machinery. This might reduce the ability of cortical and hippocampal afferents to activate MSNs, which may in turn reduce drug seeking in response to relevant cues. Future behavioral experiments should test this hypothesis.
Comparing Visual Responses in Superior Colliculus and V1
Elise L. Savier, Hui Chen, and Jianhua Cang
(see pages 9360–9368)
The superior colliculus integrates information from multiple sensory modalities and uses the information to direct orienting responses, such as saccades or head turns, toward salient stimuli. The best studied inputs to the superior colliculus are from visual areas, including the retina. More than 85% of retinal ganglion cells in mice send direction projections to the superior colliculus. These afferents target the most superficial layer, the stratum griseum superficiale (SGS), where they form a topographic map similar to that in primary visual cortex (V1). The response properties of mouse SGS neurons are also similar to those in V1: for example, they have ON/OFF receptive fields and show orientation, direction, and spatial frequency tuning. Given these similarities, Savier et al. asked whether SGS responses, like those in V1, are modulated by locomotion.
To answer this question, the authors used two-photon calcium imaging to measure V1 and SGS responses to visual patterns as head-fixed mice walked freely on a cylindrical treadmill. Consistent with previous work, visual responses in V1 neurons were much larger (∼180%) when mice were running than when they were stationary. Locomotion had a much weaker effect on visual responses in SGS, however. Responses were modulated by locomotion in only ∼30% of SGS neurons, and this included both increases and decreases in response amplitude, with an average increase of only ∼10%. Interestingly, responses to stimuli moving in the preferred direction of neurons tended to decrease during locomotion, whereas responses to stimuli moving in the opposite direction increased. Consequently, overall direction selectivity decreased during locomotion. The authors also found that spontaneous activity was lower in SGS than in V1 and that responses were more consistent across multiple presentations of the same stimulus in SGS than in V1.
These results suggest that SGS neurons provide a representation of visual stimuli that is less influenced by behavioral state than the representation in V1. This may help animals make more accurate orienting responses to stimuli. It remains possible, however, that state dependence emerges in deeper layers of the superior colliculus. Future work must investigate this possibility.
Footnotes
This Week in The Journal was written by Teresa Esch, Ph.D.
