GABAergic inhibition in the neostriatum

https://doi.org/10.1016/S0079-6123(06)60006-XGet rights and content

Abstract

In the neostriatum, GABAergic inhibition arises from the action of at least two classes of inhibitory interneurons, and from recurrent collaterals of the principal cells. Interneurons receive excitatory input only from extrinsic sources, and so act in a purely feedforward capacity. Feedback inhibition arises from the recurrent collaterals of the principal cells. These two kinds of inhibition have functionally distinct effects on the principal cells. Inputs from interneurons are not very convergent. There are few inhibitory neurons, and so each principal cell receives inhibitory synaptic input from very few interneurons. But, they are individually powerful, and a single interneuron can substantially delay action potentials in a group of nearby principal cells. Recurrent inhibition is highly convergent, with each principal cell receiving inhibitory input from several hundred other such cells. Feedback inhibitory synaptic inputs individually have very weak effects, as seen from the soma. The differences in synaptic strength are not caused by differences in the release of transmitter or in sensitivity of the postsynaptic membrane. Rather, they arise from differences in the number of synaptic contacts formed on individual principal cells by feedforward or feedback axons, and from differences in synaptic location. Interneurons form their powerful synapses near the somata of principal cells, while most feedback synapses are more distal, where they interact with the two-state nonlinear properties of the principal cells’ dendrite. This arrangement suggests that feedforward inhibition may serve in the traditional role for inhibition, adjusting the excitability of the principle neuron near the site of action potential generation. Feedback inhibitory synapses may interact with voltage-sensitive conductances in the dendrite to alter the electrotonic structure of the spiny cell.

Section snippets

Most striatal neurons are GABAergic, but most striatal synapses are not

The striatum apparently possesses no native species of excitatory neuron. With the exception of the cholinergic interneuron, all the cell types so far identified in the striatum are GABAergic, and presumably inhibitory in function. This includes both interneurons and the principal cells. The abundant principal neurons of the striatum, the spiny (Sp) cells, which constitute the vast majority of the neurons, are of two types. The two subclasses are present in approximately equal proportions and

Spatial distribution of GABAergic synapses on spiny cells

It would be useful to know how many GABAergic synapses there are on each Sp projection neuron, and what proportion of these originates from interneurons and what from other projection cells. GABAergic axons arising from the Sp cells and interneurons form symmetrical synapses. Symmetrical contacts account for about 20% of all synapses in the striatum (Ingham et al., 1998). Assuming that most of these are on Sp cells, it would suggest that there are about 2500 symmetrical synapses per Sp cell.

How can inhibition be effective when so outnumbered?

If inhibition is to be effective in controlling the effects of the massive excitatory innervation of the Sp cell, it must be either because few excitatory inputs are active at any one time, or because inhibitory synapses are given some advantage over excitation, for example a larger or more long-lived conductance change, a higher probability of transmitter release, or a more advantageous location on the neuron. The effectiveness of synapses formed by GABAergic interneurons may rely in part on

Feedforward and feedback inhibition

Feedback and feedforward inhibition are separated in the striatum by the inhibitory nature of the Sp cell. Although collaterals of the Sp cells may make synaptic contacts with FS and SOM interneurons and so may influence the feedforward pathways, they do not excite those cells and so cannot evoke lateral inhibition through that pathway. The Sp cells, via their connections among each other, exclusively control feedback inhibition. To be faithful to the original meaning of these words,

Winner-take-all inhibition in the striatum?

Feedback inhibition has often been proposed to play an important functional role in the striatum (e.g., Wickens, 1993; Rolls and Treves, 1998; Plenz and Kitai, 2000; Bar-Gad and Bergman, 2001). Feedback inhibition can offer a powerful computational advantage in a network of neurons receiving a common set of afferents, and having a mechanism of use-dependent synaptic plasticity in the input pathway. If the inhibition is strong enough to limit the number of neurons that can respond to any one

Could groups of spiny cells compete with each other?

Starting with the Tunstall et al. (2002) paper, an effort was made to measure the connectivity among Sp cells. The results consistently showed a connectivity of about 0.16, that is, any particular Sp neuron is found to make synapses with about 1/6 of its nearby neighbours. This high connectivity indicates that every Sp neuron receives many synapses from other Sp neurons. Assuming an axonal field of about 400 μm diameter, and a connectivity of 1/6, each Sp neuron would receive synapses from about

Inhibition and the mechanism of up and down states in vivo

In vivo, the membrane potentials of Sp neurons transition between the Up and Down states under the influence of synaptic inputs. In unanesthetized animals, the transitions are irregular, and cells can spend minutes in the Down state (Wilson and Groves, 1981). In animals anesthetized with urethane, or with ketamine, highly organized slow rhythmic changes in cortical activity imposes similar slow changes in Sp neurons, making it relatively easy to study these transitions (Wilson and Kawaguchi,

Why is Sp→Sp inhibition so weak?

Although the functional implications of fast, powerful and non-convergent feedforward inhibition and weak convergent feedback are not known, we do know the cellular reasons why the strengths of FS→Sp and Sp→Sp synapses are so different. Kóos et al. (2004) studied the reasons for the strength of FS→Sp cell synapses, using quantal analysis to compare the synapses on Sp cells derived from FS cells to the weaker synapses formed by Sp cells. These experiments showed that the conductance change

The reversal potential of GABAA

The reversal potential of GABAA inhibition in Sp cells has repeatedly been shown to be positive to the resting potential, and negative to the action potential threshold, resulting in depolarizing IPSPs when measured in slices at the resting potential (Misgeld et al., 1982; Plenz, 2003; Bracci and Panzeri, 2006). Measurements of the reversal potential of GABAA IPSCs in gramicidin perforated patch recordings in slices have confirmed that the chloride equilibrium potential in Sp neurons lies

Dendritic inhibition probably acts in the dendrites

Although the inhibition exerted by Sp cell synapses is small when viewed from the Sp cell soma, it is very large at locations in the dendrite near the synapse. Possibly, the large local IPSPs generated by these synapses may exert a function not fully appreciated from the soma, or from the site of action potential generation. One possible dendritic effect of inhibition is suggested by the nonlinear membrane characteristics of the cell in the subthreshold range. As described above, the membrane

References (72)

  • J.J. Soghomonian et al.

    Serotonin innervation in adult rat neostriatum. II. Ultrastructural features: a radioautographic and immunocytochemical study

    Brain Res.

    (1989)
  • H.B. Wang et al.

    Single-cell RT-PCR, in situ hybridization histochemical, and immunohistochemical studies of substance P and enkephalin co-occurrence in striatal projection neurons in rats

    J. Chem. Neuroanat.

    (2006)
  • C.J. Wilson

    Postsynaptic potentials evoked in spiny neostriatal neurons by stimulation of ipsilateral and contralateral cortex

    Brain Res.

    (1986)
  • C.J. Wilson et al.

    Spontaneous firing patterns of identified spiny neurons in the rat neostriatum

    Brain Res.

    (1981)
  • Z.C. Xu et al.

    Restoration of the corticostriatal projection in rat neostriatal grafts: electron microscopic analysis

    Neuroscience

    (1989)
  • N. Aronin et al.

    Glutamic acid decarboxylase and enkephalin immunoreactive axon terminals in the rat neostriatum synapse with striatonigral neurons

    Brain Res.

    (1986)
  • E. Bracci et al.

    Excitatory GABAergic effects in striatal projection neurons

    J. Neurophysiol.

    (2006)
  • M.D. Bevan et al.

    Selective innervation of neostriatal interneurons by a subclass of neuron in the globus pallidus of the rat

    J. Neurosci.

    (1998)
  • J.P. Bolam et al.

    The postsynaptic targets of substance P-immunoreactive terminals in the rat neostriatum with particular reference to identified spiny striatonigral neurons

    Exp. Brain Res.

    (1988)
  • R.M. Bruno et al.

    Feedforward mechanisms of excitatory and inhibitory cortical receptive fields

    J. Neurosci.

    (2002)
  • D. Centonze et al.

    Dopamine, acetylcholine and nitric oxide systems interact to induce corticostriatal synaptic plasticity

    Rev. Neurosci.

    (2003)
  • R.L. Cowan et al.

    Spontaneous firing patterns and axonal projections of single corticostriatal neurons in the rat medial agranular cortex

    J. Neurophysiol.

    (1994)
  • U. Czubayko et al.

    Fast synaptic transmission between striatal spiny projection neurons

    Proc. Natl. Acad. Sci. USA

    (2002)
  • L. Dube et al.

    Identification of synaptic terminals of thalamic or cortical origin in contact with distinct medium-size spiny neurons in the rat neostriatum

    J. Comp. Neurol.

    (1988)
  • J.N. Guzman et al.

    Dopaminergic modulation of axon collaterals interconnecting spiny neurons of the rat striatum

    J. Neurosci.

    (2003)
  • N. Gustafson et al.

    A comparative voltage and current-clamp analysis of feedback and feedforward synaptic transmission in the striatal microcircuit in vitro

    J. Neurophysiol.

    (2005)
  • J.A. Hertz et al.

    Introduction to the Theory of Neural Computation

    (1991)
  • S. Hernandez-Lopez et al.

    D2 dopamine receptors in striatal medium spiny neurons reduce L-type Ca2+ currents and excitability via a novel PLC[beta]1-IP3-calcineurin-signaling cascade

    J. Neurosci.

    (2000)
  • C.A. Ingham et al.

    Plasticity of synapses in the rat neostriatum after unilateral lesion of the nigrostriatal dopaminergic pathway

    J. Neurosci.

    (1998)
  • P.N. Izzo et al.

    Cholinergic synaptic input to different parts of spiny striatonigral neurons in the rat

    J. Comp. Neurol.

    (1988)
  • D. Jaeger et al.

    Surround inhibition among projection neurons is weak or nonexistent in the rat neostriatum

    J. Neurophysiol.

    (1994)
  • Y. Kawaguchi

    Physiological, morphological and histochemical characterization of three classes of interneurons in rat neostriatum

    J. Neurosci.

    (1993)
  • Y. Kawaguchi et al.

    Intracellular recording of identified neostriatal patch and matrix spiny cells in a slice preparation preserving cortical inputs

    J. Neurophysiol.

    (1989)
  • Y. Kawaguchi et al.

    Projection subtypes of rat neostriatal matrix cells revealed by intracellular injection of biocytin

    J. Neurosci.

    (1990)
  • J.M. Kemp et al.

    The synaptic organization of the caudate nucleus

    Phil. Trans. R. Soc. Lond. B.

    (1971)
  • J.M. Kemp et al.

    The site of termination of afferent fibres in the caudate nucleus

    Phil. Trans. R. Soc. Lond. B.

    (1971)
  • Cited by (115)

    • Striatal bilateral control of skilled forelimb movement

      2021, Cell Reports
      Citation Excerpt :

      In addition to their final targets, SPNs also connect locally via extensive axon collaterals that inhibit neighboring neurons (López-Huerta et al., 2013; Taverna et al., 2004; Tepper et al., 2008). Connections between D1 and D2 receptor-expressing SPNs are thought to regulate intrastriatal information processing units that govern the final basal ganglion output (Tepper et al., 2008; Wilson, 2007). In this study, we used selective optogenetic manipulation of striatal output neurons during performance of a unimanual skilled motor task.

    View all citing articles on Scopus
    View full text