Trends in Neurosciences
OpinionOver-inhibition: a model for developmental intellectual disability
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.
References (80)
The neurobiological consequences of Down syndrome
Brain Res. Bull.
(1986)- et al.
Is mental retardation a defect of synapse structure and function?
Pediatr. Neurol.
(2003) - et al.
Hebb and homeostasis in neuronal plasticity
Curr. Opin. Neurobiol.
(2000) Morphological correlates of altered neuronal activity in organotypic cultures chronically exposed to anti-GABA agents
Brain Res. Dev. Brain Res.
(1994)- et al.
Evidence for a role of dendritic filopodia in synaptogenesis and spine formation
Neuron
(1996) Activity coregulates quantal AMPA and NMDA currents at neocortical synapses
Neuron
(2000)The HMG-CoA reductase inhibitor Lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1
Curr. Biol.
(2005)Effects of prenatal protein malnutrition on the hippocampal formation
Neurosci. Biobehav. Rev.
(2002)Developmental protein malnutrition in the rat: Effects on single-unit activity in the frontal cortex
Brain Res.
(1984)Spontaneous forebrain neuronal activity in developmentally protein malnourished rats
Brain Res.
(1983)
Prenatal protein malnutrition alters synaptic mechanisms of callosal connections in the rat visual cortex
Int. J. Dev. Neurosci.
Prenatal protein deprivation in rats induces changes in prepulse inhibition and NMDA receptor binding
Brain Res.
Prenatal protein malnutrition enhances stimulus control by CDP, but not a CDP/THIP combination in rats
Pharmacol. Biochem. Behav.
MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin
Cell
Hippocampal synaptic plasticity is impaired in the Mecp2-null mouse model of Rett syndrome
Neurobiol. Dis.
The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression
Neuron
Synaptic deficit in the temporal cortex of partial trisomy 16 Ts65Dn mice
Brain Res.
Increased synaptic depression in the Ts65Dn mouse, a model for mental retardation in Down syndrome
Neuropharmacology
Frontal cortex BDNF levels correlate with working memory in an animal model of Down syndrome
Behav. Brain Res.
The mGluR theory of fragile X mental retardation
Trends Neurosci.
Pharmacological rescue of synaptic plasticity, courtship behavior, and mushroom body defects in a Drosophila model of fragile X syndrome
Neuron
Suppression of two major Fragile X syndrome mouse model phenotypes by the mGluR5 antagonist MPEP
Neuropharmacology
The kindling model of epilepsy: A review
Prog. Neurobiol.
Seizure-triggering mechanisms in the kindling model of epilepsy: Collapse of GABA-mediated inhibition and activation of NMDA receptors
Neurosci. Biobehav. Rev.
Effects of protein synthesis inhibition on kindling in the mouse
Exp. Neurol.
GABAergic excitation promotes neuronal differentiation in adult hippocampal progenitor cells
Neuron
Excitation-neurogenesis coupling in adult neural stem/progenitor cells
Neuron
Chronic administration of flumazenil increases life span and protects rats from age-related loss of cognitive functions: A benzodiazepine/GABAergic hypothesis of brain aging
Neurobiol. Aging
Seizures in neurofibromatosis 1
Pediatr. Neurol.
Epilepsy and associated effects on adaptive behaviour in adults with Down syndrome
Seizure
Down syndrome, Alzheimer's disease and seizures
Brain Dev.
Effects of prenatal protein malnutrition on perforant path kindling in the rat
Brain Res.
Abnormal cerebral cortical neurons in a child with maternal PKU syndrome
J. Child Neurol.
Dendritic spine pathology in infants with severe protein–calorie malnutrition
Pediatrics
Reduction in number of immunostained GABAergic neurones in deprived-eye dominance columns of monkey area 17
Nature
Miniature synaptic events maintain dendritic spines via AMPA receptor activation
Nat. Neurosci.
Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system
Nat. Neurosci.
Activity-dependent regulation of GABAA receptors
Ann. N. Y. Acad. Sci.
Impaired glutamatergic synaptic transmission in the PKU brain
Mol. Genet. Metab.
Functional neuroanatomy of visuospatial working memory in fragile X syndrome: relation to behavioral and molecular measures
Am. J. Psychiatry
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