Functional regulation of the dentate gyrus by GABA-mediated inhibition

doi:10.1016/S0079-6123(07)63014-3

Progress in Brain Research

Volume 163, 2007, Pages 235-243, 812

https://doi.org/10.1016/S0079-6123(07)63014-3 Get rights and content

Abstract

Dentate granule cells are characterized by their low levels of excitability, an important aspect of hippocampal function, which distinguishes them from other principal cells of the hippocampus. This low excitability derives in large part from the degree and nature of GABAergic inhibition evident in the dentate gyrus. Granule cells express a unique and complex assortment of GABA_A receptor subunits, found in few areas of the brain. Associated with this receptor complexity, granule cells are endowed with both synaptic and extrasynaptic GABA_A receptors with distinctive properties. In particular, extrasynaptic GABA_A receptors in granule cells exhibit high affinity for GABA and do not desensitize. This results in activation of a tonic current by ambient levels of GABA present in the extracellular space. This tonic current contributes significantly to the circuit properties of the dentate gyrus. Both synaptic and extrasynaptic GABA_A receptors exhibit profound dysregulation in animal models of temporal lobe epilepsy, which may contribute to the hippocampal hyperexcitability that defines this disorder.

Introduction

As a part of its role in memory formation, the hippocampus encodes a cognitive map of the space in which an animal (or human) navigates. During environmental exploration, studies recording place fields in rat hippocampal neurons have typically demonstrated that information coding of spatial position (i.e. degree of firing and firing patterns) is specific but sparse in dentate granule cells (Jung and McNaughton, 1993; Chawla et al., 2005) compared to dorsal hippocampal pyramidal cells (O’Keefe, 1976; Wilson and McNaughton, 1993). This ‘sparse coding’ of dentate granule cells is theorized to be important in information processing and memory formation of the hippocampus (McNaughton and Morris, 1987). It also reflects a general trend evident in most studies of dentate granule cell excitability: these cells exhibit a fundamental reluctance to fire, particularly synchronously in network bursts. This is due, in part, to a combination of intrinsic factors (including hyperpolarized resting membrane potential, lack of conductances which permit phasic firing or “bursting”, and marked spike frequency adaptation), but is principally a consequence of the powerful feedforward and feedback GABAergic inhibition characteristic of dentate gyrus circuit function.

In addition to its important role in cognitive processing, the low excitability of the dentate gyrus may serve to filter or ‘gate’ synchronous excitatory activity in entorhinal cortex, preventing this type of activity from hyperactivating and damaging the relatively fragile hippocampal structures downstream, and from triggering seizure activity (Heinemann et al., 1992; Lothman et al., 1992). Like sparse coding, this gating function of the dentate gyrus is also due to powerful feedforward and feedback GABAergic inhibition, as well as intrinsic properties of granule cells. Furthermore, the filter function of the dentate gyrus may be compromised in animals with epilepsy, or in animals in the process of developing epilepsy, and this loss of function may reflect alterations in GABA_A receptor expression and function in dentate granule cells. The intent of the present chapter is to discuss dentate gyrus circuit excitability in context of the GABA receptors, which granule cells express, and also to extend this discussion to how alterations in expression and function of inhibitory synaptic receptors in epileptic animals may disrupt normal operation of the dentate gyrus.

Section snippets

Heterogeneous composition and function of GABA_A receptors in the CNS

GABA_A receptors are members of the cysteine-loop ligand-gated ion channel family, which, like other members of this family, are pentameric assemblies of subunits that surround a central ion selective pore. The properties of the pore in GABA receptors make it primarily permeable to chloride and bicarbonate ions. The net result of activation of GABA receptors is therefore flow of chloride into cells down its concentration gradient, concomitant hyperpolarization of the membrane potential, and a

GABA_A receptors expressed by dentate granule cells

In situ hybridization (Wisden et al., 1992), immunocytochemical (Sperk et al., 1997; Pirker et al., 2000), and single-cell combined antisense RNA amplification profiling-functional studies (Brooks-Kayal et al., 1998) have demonstrated that granule cells express as many as 10 or more GABA_A receptor subunits, even when only a single cell is measured (Brooks-Kayal et al., 1998). Of 19 possible subunits, technological and experimental issues have limited profiling to 13 subunits or less in most

Tonic and phasic inhibition in dentate granule cells

In addition to synaptic GABA_A receptors, which demonstrate a significant contribution of α1 subunits, dentate granule cells express a relatively unique set of GABA_A receptors comprised of α4βδ subunits. Receptors with this composition are only found to any significant extent in one other region of the brain, the thalamus, where they are expressed in thalamocortical relay neurons (McKernan and Whiting, 1996). These two brain regions, the dentate gyrus and the thalamus, share a functional

The ‘gatekeeper’ function of the dentate gyrus is maintained by GABAergic inhibition

Assessing the role of GABAergic inhibition in regulating function of the dentate gyrus requires simultaneous recording in afferents to the dentate gyrus, the dentate gyrus itself, and efferents of the dentate gyrus during synaptic activation. This is necessary to ascertain how the dentate gyrus circuitry may filter and constrain the amplitude and duration of afferent inputs as it passes information on to area CA3 of the hippocampus. In addition, these recordings need to be conducted under

Alterations in GABA_A receptor expression in dentate granule cells, and function of the dentate gyrus in animal models of epilepsy

Temporal lobe epilepsy is defined by seizures discharges which activate the temporal lobe, including the hippocampus. Because the dentate gyrus is hypothesized to be a critical checkpoint regulating excitability of the limbic system (Heinemann et al., 1992; Lothman et al., 1992), it has been a focus of multiple studies in animal models of epilepsy, assessing whether cellular, synaptic, and circuit properties are altered in a manner consistent with seizure susceptibility. A primary focus of this

Upregulation of synaptic GABA_A receptors in granule cells of epileptic animals

If levels of GABAergic inhibition are critical in mediating gatekeeper function of the dentate gyrus, and compromised filter function of the dentate is a primary contributor to seizure generation in animals with temporal lobe epilepsy, then one might expect that overall levels of expression of GABA_A receptors might be reduced in epileptic animals. In both kindling and post-status epilepticus models of temporal lobe epilepsy, studies examining GABA_A receptor function in dentate granule cells

Alterations in pharmacology and subunit expression of dentate granule cell GABA_A receptors in epileptic animals

This upregulation of GABA_A receptors appears to be inconsistent with the hypothesis that compromised inhibition in the dentate gyrus might contribute to seizure generation in epileptic animals. However, experimental evidence provides additional clues as to how alterations in inhibition may contribute to seizure susceptibility. Not only is there an upregulation in density of GABA_A receptors (discussed above), but the nature (subunit composition) of the receptors themselves is altered. This is

Possible consequences of epilepsy-associated altered subunit composition of GABA_A receptors: zinc-induced collapse of augmented inhibition

This altered zinc sensitivity of GABA_A receptors in animals with epilepsy may have functional significance. In addition to alterations in inhibitory synaptic responses, the dentate gyrus of animals with epilepsy frequently demonstrates aberrant sprouting of the output axons of granule cells, the mossy fibers. These axons, perhaps in response to loss of targets in the hilus and area CA3, sprout and reinnervate the proximal dendritic tree of other dentate granule cells, creating a reentrant

Reductions in tonic GABA_A current in granule cells of epileptic animals

A second finding has recently been described in animal models of temporal lobe epilepsy: reduction in tonic GABA_A receptor current accompanied by a downregulation in expression of δ subunits (Peng et al., 2004). Given that tonic GABA_A receptors appear critical in ‘gatekeeper’ function of the dentate gyrus, this downregulation in δ subunit expression could compromise function of the dentate gyrus, despite the concomitant upregulation of synaptic GABA_A receptors. However, recent circuit studies

Conclusions

The dentate gyrus is a structure characterized by low cellular excitability of its output neurons, dentate granule cells. This low excitability is important in cognitive function of the hippocampus, and results predominantly from the high degree of inhibitory synaptic regulation, as well as the unique GABA_A receptor properties of these cells, including expression of tonic GABA_A receptors rarely expressed in other brain regions. Altered expression and function of GABA_A receptors in dentate

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Functional regulation of the dentate gyrus by GABA-mediated inhibition

Abstract

Introduction

Section snippets

Heterogeneous composition and function of GABAA receptors in the CNS

GABAA receptors expressed by dentate granule cells

Tonic and phasic inhibition in dentate granule cells

The ‘gatekeeper’ function of the dentate gyrus is maintained by GABAergic inhibition

Alterations in GABAA receptor expression in dentate granule cells, and function of the dentate gyrus in animal models of epilepsy

Upregulation of synaptic GABAA receptors in granule cells of epileptic animals

Alterations in pharmacology and subunit expression of dentate granule cell GABAA receptors in epileptic animals

Possible consequences of epilepsy-associated altered subunit composition of GABAA receptors: zinc-induced collapse of augmented inhibition

Reductions in tonic GABAA current in granule cells of epileptic animals

Conclusions

Exp. Neurol.

Trends Neurosci.

Trends Neurosci.

Neuroscience

Neuroscience

Brain Res.

Massive and specific dysregulation of direct cortical input to the hippocampus in temporal lobe epilepsy

J. Neurosci.

Enhanced propagation of epileptiform activity through the kindled dentate gyrus

J. Neurophysiol.

Selective changes in single cell GABAA receptor subunit expression and function in temporal lobe epilepsy

Nat. Med.

Zinc-induced collapse of augmented inhibition by GABA in a temporal lobe epilepsy model

Science

Zinc facilitates hyperexcitability in the hippocampus of epileptic rats

Epilepsia

The role of inhibition and dentate gatekeeper function: voltage-sensitive dye imaging study

Soc. Neurosci. Abstr.

GABAA receptor α4 subunits mediate extrasynaptic inhibition in thalamus and dentate gyrus and the action of gaboxadol

PNAS

Sparse, environmentally selective expression of Arc RNA in the upper blade of the rodent fascia dentate by brief spatial experience

Hippocampus

Dentate granule cell GABAA receptors in epileptic hippocampus: enhanced synaptic efficacy and altered pharmacology

Eur. J. Neurosci.

Mossy fiber zinc and temporal lobe epilepsy: pathological association with altered epileptic GABAA receptors in dentate granule cells

Epilepsia

Postsynaptic clustering of major GABAA receptor subtypes requires the gamma 2 subunit and gephyrin

Nat. Neurosci.

Variations on an inhibitory theme: phasic and tonic activation of GABAA receptors

Nat. Rev. Neurosci.

Heterogeneous composition and function of GABA_A receptors in the CNS

GABA_A receptors expressed by dentate granule cells

Alterations in GABA_A receptor expression in dentate granule cells, and function of the dentate gyrus in animal models of epilepsy

Upregulation of synaptic GABA_A receptors in granule cells of epileptic animals

Alterations in pharmacology and subunit expression of dentate granule cell GABA_A receptors in epileptic animals

Possible consequences of epilepsy-associated altered subunit composition of GABA_A receptors: zinc-induced collapse of augmented inhibition

Reductions in tonic GABA_A current in granule cells of epileptic animals

Selective changes in single cell GABA_A receptor subunit expression and function in temporal lobe epilepsy

GABA_A receptor α4 subunits mediate extrasynaptic inhibition in thalamus and dentate gyrus and the action of gaboxadol

Dentate granule cell GABA_A receptors in epileptic hippocampus: enhanced synaptic efficacy and altered pharmacology

Mossy fiber zinc and temporal lobe epilepsy: pathological association with altered epileptic GABA_A receptors in dentate granule cells

Postsynaptic clustering of major GABA_A receptor subtypes requires the gamma 2 subunit and gephyrin

Variations on an inhibitory theme: phasic and tonic activation of GABA_A receptors