Proteomic characterization of spinal cord synaptoneurosomes from Tg-SOD1/G93A mice supports a role for MNK1 and local translation in the early stages of amyotrophic lateral sclerosis.

The isolation of synaptoneurosomes (SNs) represents a useful means to study synaptic events. However, the size and density of synapses varies in different regions of the central nervous system (CNS), and this also depends on the experimental species studied, making it difficult to define a generic protocol for SNs preparation. To characterize synaptic failure in the spinal cord (SC) in the Tg-SOD1/G93A mouse model of amyotrophic lateral sclerosis (ALS), we applied a method we originally designed to isolate cortical and hippocampal SNs to SC tissue.

Prenatal treatment with rapamycin restores enhanced hippocampal mGluR-LTD and mushroom spine size in a Down's syndrome mouse model.

Down syndrome (DS) is the most frequent genetic cause of intellectual disability including hippocampal-dependent memory deficits. We have previously reported hippocampal mTOR (mammalian target of rapamycin) hyperactivation, and related plasticity as well as memory deficits in Ts1Cje mice, a DS experimental model. Here we characterize the proteome of hippocampal synaptoneurosomes (SNs) from these mice, and found a predicted alteration of synaptic plasticity pathways, including long term depression (LTD).

CPEB1 is overexpressed in neurons derived from Down syndrome IPSCs and in the hippocampus of the mouse model Ts1Cje.

Trisomy 21, also known as Down syndrome (DS), is the most frequent genetic cause of intellectual impairment. In mouse models of DS, deficits in hippocampal synaptic plasticity have been observed, in conjunction with alterations to local dendritic translation that are likely to influence plasticity, learning and memory. Here we show that expression of a local translational regulator, the Cytoplasmic Polyadenylation Element Binding Protein 1 (CPEB1), is enhanced in hippocampal neurons from the Ts1Cje DS mouse model.

Proteomic Analysis of Synaptoneurosomes Highlights the Relevant Role of Local Translation in the Hippocampus.

Several proteomic analyses have been performed on synaptic fractions isolated from cortex or even total brain, resulting in preparations with a high synaptic heterogeneity and complexity. Synaptoneurosomes (SNs) are subcellular membranous elements that contain sealed pre- and post-synaptic components. They are obtained by subcellular fractionation of brain homogenates and serve as a suitable model to study many aspects of the synapse physiology.

Rapamycin restores BDNF-LTP and the persistence of long-term memory in a model of Down's syndrome.

Down's syndrome (DS) is the most prevalent genetic intellectual disability. Memory deficits significantly contribute to the cognitive dysfunction in DS. Previously, we discovered that mTOR-dependent local translation, a pivotal process for some forms of synaptic plasticity, is deregulated in a DS mouse model.

The Akt-mTOR pathway in Down's syndrome: the potential use of rapamycin/rapalogs for treating cognitive deficits.

An increasing amount of evidence suggests that the dysregulation of the Akt-mTOR (Akt-mammalian Target Of Rapamycin) signaling network is associated with intellectual disabilities, such as fragile X, tuberous sclerosis and Rett's syndrome. The Akt-mTOR pathway is involved in dendrite morphogenesis and synaptic plasticity, and it has been shown to modulate both glutamatergic and GABAergic synaptic transmission. We have recently shown that the AktmTOR pathway is hyperactive in the hippocampus of Ts1Cje mice, a model of Down's syndrome, leading to increased local dendritic translation that could interfere with synaptic plasticity.

Active zones and the readily releasable pool of synaptic vesicles at the neuromuscular junction of the mouse.

Synchronous neurotransmitter release is a highly regulated process that takes place at specializations at the presynaptic membrane called active zones (AZs). The relationships between AZs, quantal release, and vesicle replenishment are not well understood in a mature synapse. We have measured the number, distribution, and other properties of AZs in mouse motor nerve terminals and combined these observations with electrophysiological estimates of the size of the readily releasable pool (RRP) of synaptic vesicles.

Altered intracellular Ca2+ homeostasis in nerve terminals of severe spinal muscular atrophy mice.

Low levels of survival motor neuron (SMN) protein result in spinal muscular atrophy (SMA), a severe genetic disease characterized by motor impairment and premature lethality. Although SMN is a ubiquitous protein, motor neurons are much more vulnerable to low levels of SMN than other cells. To gain insight into the pathogenesis of SMA, we have compared synaptic function of motor terminals in wild-type and severe SMA mice at different ages and in two proximal muscles.