Trends in Neurosciences
Volume 30, Issue 10, October 2007, Pages 497-503
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Opinion
Over-inhibition: a model for developmental intellectual disability

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Developmental intellectual disability (DID) is a daunting societal problem. Although tremendous progress has been made in defining the genetic causes of DID, therapeutic strategies remain limited. In particular, there is a marked absence of a unified approach to treating cognitive impairments associated with DID. Here, we suggest that the brain in many DID-related disorders is subject to a basic imbalance in neuronal activity, with an increased contribution of inhibition to neural circuits. This over-inhibition, in turn, is predicted to lead to deficits in synaptic plasticity and learning and memory. We further discuss possibilities for pharmacological intervention in DID, focusing on the concept of drug-induced ‘therapeutic neuroadaptation’ as a means of stably enhancing constitutive circuit excitability and cognition over time.

Introduction

Developmental intellectual disability (DID) is a prevalent form of nonprogressive cognitive impairment, affecting 2–3% of the population in the industrialized world. Disorders involving DID, although narrowly defined by an IQ <70 and by deficits in academic, adaptive and interpersonal skills, are widely diverse in their causes. The frequency of DID-related cognitive dysfunction is alarming considering that pharmacological intervention is currently nonexistent. Historically, neuroscientists have probed the brain in DID patients for clues to possible treatment strategies for DID-related learning difficulties. In the case of Down syndrome (DS), these pioneering investigations have led to observations of neuronal cell loss, stunted dendritic branching, and spine dysgenesis [1]. Interestingly, many of the histological features noted in the brains of individuals with DS parallel phenotypes that have been found in the brains of individuals with other classes of DID, such as genetic disorders including inborn errors of metabolism [2] and non-genetic insults [3]. Similarities across the spectrum of DID-related disorders argue that common mechanisms underlie the manifestation of learning and memory deficits in intellectually disabled children and young adults [4].

Here, we present one such common, unifying mechanism: over-inhibition of the brain. We hypothesize that DID is the byproduct of long-term changes in neural excitability, driven by increases in the contribution of inhibition to neural circuits. To present our case, we first describe the concept of homeostatic plasticity, that is, the tendency of neuronal networks to counteract long-term elevations or depressions in activity. Subsequently, we use this principle to explain and integrate observations that have been made in several classes of DID disorders and in animal models of DID. Finally, with this over-inhibition model in mind, we outline a novel approach to treating DID using drug induced therapeutic neuroadaptation.

Section snippets

Homeostatic plasticity: definition

It has become increasingly clear that traditional forms of synaptic plasticity (i.e. long-term potentiation and long-term depression) can only occur in the context of stabilizing forces that allow a circuit to maintain a physiologically relevant level of activity. In the absence of such resetting, circuits would become incapable of responding. These compensatory mechanisms, collectively referred to as ‘homeostatic plasticity,’ occur over broad time scales in response to chronic excitation or

Homeostasis and developmental intellectual disability

The mammalian brain has been adapted with a comprehensive set of mechanisms integrated at the circuit, single-cell, and molecular level that functions to maintain a specific range of neuronal activity. There is mounting evidence that various forms of DID are attributed to the over-inhibition of neural circuits. Such a state is expected to compromise the capacity of the circuit to undergo forms of associative plasticity thought to underlie adult learning and memory. In the section below, we

Neurofibromatosis 1

Neurofibromatosis 1 (NF1) is attributed to genetic mutations in the NF1 gene and is clinically characterized by the appearance of neurofibroma mass lesion of the peripheral nervous system. In addition, ∼80% of affected children exhibit cognitive disabilities, including impairments in perception, executive function (ability to make decisions) and attention [15]. The mutations are associated with a loss of function of the Ras guanosine triphosphatase (RasGAP) activity of neurofibromin and this

Neonatal protein malnutrition

Similar findings in cognitive impairment induced by protein or caloric malnutrition further implicate excessive inhibition as a unifying mechanism in DID. Neonatal protein deprivation in rodents significantly raises mIPSP frequency in the cornu ammonis (CA1 and CA3) fields of the hippocampus 19, 20, and exaggerates GABAergic inhibitory responses in the dentate gyrus of freely moving animals [21]. Monitoring of discharges from single neurons in the neocortex, moreover, reveals dramatic

Rett syndrome and Down's syndrome: etiologically complicated forms of intellectual disability

At least two classes of DID disorders, resulting from genetic and non-genetic lesions, strongly support the hypothesis that excessive inhibition of neural circuits is one causative factor in neurological disorders characterized by severe intellectual disability. However, can this straightforward, unifying hypothesis account for the learning and memory deficits that plague two of the most pleiotropic DID syndromes?

Rett syndrome is a neurodevelopmental disorder generally resulting from

Setting things right: developing strategies to treat DID

Recent studies have provided compelling evidence that DID disorders brought about by single gene deletions are amenable to pharmacotherapy. For example, work in mouse models of Fragile X syndrome has suggested that loss of Fragile X mental retardation protein (FMRP) results in the amplification of group 1 metabotropic glutamate receptor (mGluR) downstream signaling, potentially leading to Fragile X-related neurological symptoms [44]. In turn, mGluR antagonists have been shown to normalize

Strategies for eliciting adaptive change in the brain

The brain is an adaptive organ, wherein changes in GABA-mediated inhibition govern the assembly of neural circuits throughout development. The maturation of GABAergic networks has not only been shown to usher the onset and offset of sensitive periods in experience-dependent developmental plasticity in the visual system 47, 48, but also to sculpt the columnar architecture of the visual cortex by shaping the geometry of incoming thalamic arbors [49]. Moreover, studies in the developing auditory

Kindling: a non-adaptive change in brain function

Described by Goddard in 1967 [55], kindling refers to an animal model of epileptogenesis in which the periodic introduction of an initially subconvulsive electrical or chemical stimulus to the brain leads to electrographic and behavioral seizure activity [55]. Once in this state, animals show a permanent (lifetime) increased sensitivity to stimulus-induced seizures, which suggests that the synaptic responsiveness of the stimulated circuits undergoes an augmentation that persists in the absence

Therapeutic neuroadaptation: an example of adaptive change relevant to DID

Kindling with high doses of GABAA receptor antagonists causes pathological changes in the CNS. Nonetheless, the neuronal interactions that are catalyzed in response to chemical kindling are present in the normal brain and could potentially be harnessed to achieve different goals. Considering that a major problem encountered in DID disorders is excess inhibition, a natural question arises as to whether it is possible to strategically maneuver a low-dose GABAA antagonist regimen to stably

Clinical context of reducing inhibitory tone

Anti-GABAergic drugs have been traditionally labeled as ‘convulsants’ or ‘anxiogenics’ because of their ability at moderately high doses to precipitate seizures and increase anxiety-related behavior [65]. On the surface, these properties appear to complicate the practical use of negative GABAA modulators. They also raise concerns over what the long-term effects of chronic drug use might be in DID populations given the prominent role of GABA in the CNS [66]. Still, studies of neurogenesis in the

Conclusions

DID results from many different genetic and environmental insults. The dissection of these various etiologies has shown in principle that changes in the expression of individual or ensembles of genes can lead to shifts in the balance of excitation and inhibition in neural circuits, thus impairing their ability to undergo the plastic processes thought essential for normal learning and memory. Interestingly, evidence for regional or global over-inhibition has been identified across several

Acknowledgements

We thank the National Science Foundation (F.F.), the National Institute of Health (F.F.) the Down's syndrome Research and Treatment Foundation (C.C.G.), the Hillblom Foundation (C.C.G.), as well as the Stanford Down syndrome Center (C.C.G.) for their support. We would also like to thank M. Blank and R.J. Reimer for a critical reading of the manuscript.

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