Basal synaptic transmission involves the release of neurotransmitters at individual synapses in response to a single action potential. Recent discoveries show that astrocytes modulate the activity of neuronal networks upon sustained and intense synaptic activity. However, their ability to regulate basal synaptic transmission remains ill defined and controversial. Here, we show that astrocytes in the hippocampal CA1 region detect synaptic activity induced by single-synaptic stimulation. Astrocyte activation occurs at functional compartments found along astrocytic processes and involves metabotropic glutamate subtype 5 receptors. In response, astrocytes increase basal synaptic transmission, as revealed by the blockade of their activity with a Ca(2+) chelator. Astrocytic modulation of basal synaptic transmission is mediated by the release of purines and the activation of presynaptic A(2A) receptors by adenosine. Our work uncovers an essential role for astrocytes in the regulation of elementary synaptic communication and provides insight into fundamental aspects of brain function.

Hyperconnectivity of neuronal circuits due to increased synaptic protein synthesis is postulated to cause Autism Spectrum Disorders (ASD). The mammalian target of rapamycin (mTOR) is strongly implicated in ASD via upstream signaling. However, downstream regulatory mechanisms are ill-defined. We show that knockout (KO) of the eukaryotic translation Initiation Factor 4E-Binding Protein 2 (4E-BP2), an eIF4E-repressor downstream of mTOR, or eIF4E overexpression lead to increased translation of neuroligins, which are post-synaptic proteins that are causally linked to ASD. 4E-BP2-KO mice exhibit an increased ratio of excitatory to inhibitory synaptic inputs and autistic-like behaviors: social interaction deficits, altered communication and repetitive/stereotyped behaviors. Pharmacological inhibition of eIF4E activity or normalization of neuroligin 1, but not neuroligin 2 protein amounts, restore the normal excitation/inhibition ratio and rectify the social behavior deficits. Thus, translational control by eIF4E regulates the synthesis of neuroligins, maintaining the excitation to inhibition balance, and its dysregulation engenders ASD-like phenotypes.

The late phase of long-term potentiation (LTP) and memory (LTM) requires new gene expression, but the molecular mechanisms that underlie these processes are not fully understood. Phosphorylation of eIF2alpha inhibits general translation but selectively stimulates translation of ATF4, a repressor of CREB-mediated late-LTP (L-LTP) and LTM. We used a pharmacogenetic bidirectional approach to examine the role of eIF2alpha phosphorylation in synaptic plasticity and behavioral learning. We show that in eIF2alpha(+/S51A) mice, in which eIF2alpha phosphorylation is reduced, the threshold for eliciting L-LTP in hippocampal slices is lowered, and memory is enhanced. In contrast, only early-LTP is evoked by repeated tetanic stimulation and LTM is impaired, when eIF2alpha phosphorylation is increased by injecting into the hippocampus a small molecule, Sal003, which prevents the dephosphorylation of eIF2alpha. These findings highlight the importance of a single phosphorylation site in eIF2alpha as a key regulator of L-LTP and LTM formation.

Tetanus-induced heterosynaptic depression in the hippocampus is a key cellular mechanism in neural networks

Studies on various forms of synaptic plasticity have demonstrated a link between mRNA translation, learning and memory. Like memory, synaptic plasticity includes an early phase which depends on modification of pre-existing proteins, and a late phase that requires transcription and synthesis of new proteins 1,2 . Activation of post-synaptic targets appears to trigger the transcription of plasticityrelated genes. The new mRNAs are either translated in the soma or transported to synapses before translation. GCN2, a key protein kinase, regulates the initiation of translation. We now report a unique feature of hippocampal slices from GCN2 -/-mice: in CA1, a single 100 Hz train induces a strong and sustained long-term potentiation (late-LTP or L-LTP), which is transcription and translation dependent. In contrast, stimulation that elicits late-LTP in wild type slices, such as four 100 Hz trains or forskolin, fails to evoke L-LTP in GCN2 -/-slices. This aberrant synaptic plasticity is mirrored in the behavior of GCN2 -/-mice in the Morris water maze: after weak training, their spatial memory is enhanced, but it is impaired after more intense training. Activated GCN2 stimulates mRNA translation of ATF4, a CREB antagonist. Accordingly, in the hippocampus of GCN2 -/-mice, the expression of ATF4 is reduced and CREB activity is increased. Our study provides genetic, physiological, behavioral and molecular evidence that GCN2 regulates synaptic plasticity, as well as learning and memory through modulation of the ATF4/CREB pathway.Translation of eukaryotic mRNAs is primarily regulated at the level of initiation 3 . Binding of the initiator tRNA, Met-tRNA i Met , to the 40S subunit is facilitated by the initiation factor 2 (eIF2) which forms a ternary complex with GTP and Met-tRNA i Met . Although phosphorylation