Environmental enrichment decreases GABAergic inhibition and improves cognitive abilities, synaptic plasticity, and visual functions in a mouse model of Down syndrome

Begenisic, Tatjana; Spolidoro, Maria; Braschi, Chiara; Baroncelli, Laura; Milanese, Marco; Pietra, Gianluca; Fabbri, Maria Elena; Bonanno, Giambattista; Cioni, Giovanni; Maffei, Lamberto; Sale, Alessandro

doi:10.3389/fncel.2011.00029

Cited by 75 publications

(67 citation statements)

References 52 publications

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“…Our data are congruent with the results obtained by Begenisic et al [6] in a Ts65Dn murine model of DS, where they demonstrated that EE was able to favor recovery from cognitive impairment, synaptic plasticity failure, and visual deficits.…”

Section: Discussionsupporting

confidence: 96%

“…The modulation of expression of crucial molecular mediators, such as IGF-1 and BDNF, has been identified as a key mechanism mediating EE effects and also confirmed in human conditions. Moreover, it has been recently reported that in a mouse model of DS, Ts65Dn line, increased sensory-motor stimulation in adulthood through EE reduces brain inhibition levels and promotes recovery of some abilities, including visual functions [6]. EE in mice by sensory-motor stimulation is similar to the technique of infant massage (IM) in humans.…”

Section: Introductionmentioning

confidence: 98%

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Effect of early multisensory massage intervention on visual functions in infants with Down syndrome

Purpura¹,

Tinelli²,

Bargagna³

et al. 2014

Early Human Development

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Section: Discussionsupporting

confidence: 96%

Section: Introductionmentioning

confidence: 98%

Effect of early multisensory massage intervention on visual functions in infants with Down syndrome

Purpura¹,

Tinelli²,

Bargagna³

et al. 2014

Early Human Development

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“…Previous studies have observed that the levels of GAD65 (another isoform of the enzyme responsible of GABA synthesis) remain unaltered in the hippocampus [22,27], but in those studies the authors found a higher degree of colocalization of synaptophysin and GAD65, suggesting a possible alteration in the proportion of excitatory and inhibitory contacts [22]. Additionally, other studies have observed and excess of GABA release in trisomic mice [53]. Other studies have observed also a higher sensitivity of inhibition, as a consequence of changes in GABA receptors and in potassium channels [27,54,55] therefore increasing the inhibition of the system.…”

Section: Neuropil Expressionmentioning

confidence: 87%

Altered Distribution of Hippocampal Interneurons in the Murine Down Syndrome Model Ts65Dn

et al. 2014

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Down Syndrome, with an incidence of one in 800 live births, is the most common genetic alteration producing intellectual disability. We have used the Ts65Dn model, that mimics some of the alterations observed in Down Syndrome. This genetic alteration induces an imbalance between excitation and inhibition that has been suggested as responsible for the cognitive impairment present in this syndrome. The hippocampus has a crucial role in memory processing and is an important area to analyze this imbalance. In this report we have analysed, in the hippocampus of Ts65Dn mice, the expression of synaptic markers: synaptophysin, vesicular glutamate transporter-1 and isoform 67 of the glutamic acid decarboxylase; and of different subtypes of inhibitory neurons (Calbindin D-28k, parvalbumin, calretinin, NPY, CCK, VIP and somatostatin). We have observed alterations in the inhibitory neuropil in the hippocampus of Ts65Dn mice. There was an excess of inhibitory puncta and a reduction of the excitatory ones. In agreement with this observation, we have observed an increase in the number of inhibitory neurons in CA1 and CA3, mainly interneurons expressing calbindin, calretinin, NPY and VIP, whereas parvalbumin cell numbers were not affected. These alterations in the number of interneurons, but especially the alterations in the proportion of the different types, may influence the normal function of inhibitory circuits and underlie the cognitive deficits observed in DS.

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“…In particular, EE rescues spatial memory and dentate gyrus LTP as well as neuronal proliferation in Ts65Dn animals (Begenisic et al, 2011; Chakrabarti et al, 2011). Moreover, cortical LTP, anxiety behavior, motor coordination and spatial learning could be rescued in MECP2 null mice by EE (Kondo et al, 2008; Nag et al, 2009; Kerr et al, 2010; Lonetti et al, 2010) with an indication that the inhibitory GABAergic system could be preferentially responsible for the effect (Boggio et al, 2010; Lonetti et al, 2010).…”

Section: Gabaergic Therapies: Toward Innovation and Beyondmentioning

confidence: 99%

Modulation of GABAergic transmission in development and neurodevelopmental disorders: investigating physiology and pathology to gain therapeutic perspectives

Deidda

Bozarth

Cancedda

2014

Front. Cell. Neurosci.

163

160

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During mammalian ontogenesis, the neurotransmitter GABA is a fundamental regulator of neuronal networks. In neuronal development, GABAergic signaling regulates neural proliferation, migration, differentiation, and neuronal-network wiring. In the adult, GABA orchestrates the activity of different neuronal cell-types largely interconnected, by powerfully modulating synaptic activity. GABA exerts these functions by binding to chloride-permeable ionotropic GABAA receptors and metabotropic GABAB receptors. According to its functional importance during development, GABA is implicated in a number of neurodevelopmental disorders such as autism, Fragile X, Rett syndrome, Down syndrome, schizophrenia, Tourette's syndrome and neurofibromatosis. The strength and polarity of GABAergic transmission is continuously modulated during physiological, but also pathological conditions. For GABAergic transmission through GABAA receptors, strength regulation is achieved by different mechanisms such as modulation of GABAA receptors themselves, variation of intracellular chloride concentration, and alteration in GABA metabolism. In the never-ending effort to find possible treatments for GABA-related neurological diseases, of great importance would be modulating GABAergic transmission in a safe and possibly physiological way, without the dangers of either silencing network activity or causing epileptic seizures. In this review, we will discuss the different ways to modulate GABAergic transmission normally at work both during physiological and pathological conditions. Our aim is to highlight new research perspectives for therapeutic treatments that reinstate natural and physiological brain functions in neuro-pathological conditions.

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Environmental enrichment decreases GABAergic inhibition and improves cognitive abilities, synaptic plasticity, and visual functions in a mouse model of Down syndrome

Cited by 75 publications

References 52 publications

Effect of early multisensory massage intervention on visual functions in infants with Down syndrome

Effect of early multisensory massage intervention on visual functions in infants with Down syndrome

Altered Distribution of Hippocampal Interneurons in the Murine Down Syndrome Model Ts65Dn

Modulation of GABAergic transmission in development and neurodevelopmental disorders: investigating physiology and pathology to gain therapeutic perspectives

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