Learning and Memory and Synaptic Plasticity Are Impaired in a Mouse Model of Rett Syndrome

Abstract

Loss-of-function mutations or abnormal expression of the X-linked gene encoding methyl CpG binding protein 2 (MeCP2) cause a spectrum of postnatal neurodevelopmental disorders including Rett syndrome (RTT), nonsyndromic mental retardation, learning disability, and autism. Mice expressing a truncated allele of Mecp2 (Mecp2 308 ) reproduce the motor and social behavior abnormalities of RTT; however, it is not known whether learning deficits are present in these animals. We investigated learning and memory, neuronal morphology, and synaptic function in Mecp2 308 mice. Hippocampus-dependent spatial memory, contextual fear memory, and social memory were significantly impaired in Mecp2 308 mutant males (Mecp2 308/Y ). The morphology of dendritic arborizations, the biochemical composition of synaptosomes and postsynaptic densities, and brain-derived neurotrophic factor expression were not altered in these mice. However, reduced postsynaptic density cross-sectional length was identified in asymmetric synapses of area CA1 of the hippocampus. In the hippocampus of symptomatic Mecp2 308/Y mice, Schaffer-collateral synapses exhibited enhanced basal synaptic transmission and decreased paired-pulse facilitation, suggesting that neurotransmitter release was enhanced. Schaffer-collateral long-term potentiation (LTP) was impaired. LTP was also reduced in the motor and sensory regions of the neocortex. Finally, very early symptomatic Mecp2 308/Y mice had increased basal synaptic transmission and deficits in the induction of long-term depression. These data demonstrate a requirement for MeCP2 in learning and memory and suggest that functional and ultrastructural synaptic dysfunction is an early event in the pathogenesis of RTT.

Enhancing Rehabilitative Therapies with Vagus Nerve Stimulation

“…VNS, if paired with the appropriate regimen of behavioral exposure or cognitive training, may represent a potential intervention to improve these disorders. Plasticity is a core deficit in many postnatal developmental disorders, including autism and forms of mental retardation [106][107][108][109]. Rehabilitative therapies do provide benefits in patients with postnatal developmental disorders.…”

Nurturing brain plasticity: impact of environmental enrichment

“…[131][132][133][134] Electrophysiological studies from MeCP2 transgenic mice reported reduced neuronal activity in cortical 135 and hippocampal 136 neurons, suggesting that a shift in the balance between inhibition and excitation could be responsible for rapid motor, behavioural and cognitive regression typical of ReS. 137 MeCP2-deficient mice have attenuated ability to express LTP in the hippocampus 136,138 and in the motor and somatosensory cortex. 138 Importantly, the gene encoding BDNF is under MeCP2 regulation, 139 and the progression of symptoms in MeCP2-deficient mice seems to be correlated with gradually decreasing levels of circulating BDNF.…”

Advances in behavioral genetics: mouse models of autism

“…79 The mutant mice have also been characterized by deficits in long-term social memory, observed following the repeated presentation of a juvenile mouse across several days. 80,81 Other behavioral abnormalities in Mecp2 308/y mice include deficits in nest building and other home cage activity, alterations in diurnal motor patterns, 79 and impaired learning and memory. 81 An abnormal phenotype is still observed when the loss of Mecp2 is limited to forebrain areas and to postnatal development.…”

“…80,81 Other behavioral abnormalities in Mecp2 308/y mice include deficits in nest building and other home cage activity, alterations in diurnal motor patterns, 79 and impaired learning and memory. 81 An abnormal phenotype is still observed when the loss of Mecp2 is limited to forebrain areas and to postnatal development. 75,80 In particular, the conditional Mecp2-null mice still show forelimb and hindlimb clasping, motor impairment and ataxic gait, and decreased social preference.…”