Active synapses can reduce the probability of transmitter release at neighbouring synapses. Depending on whether such heterosynaptic depression is mediated by intersynaptic diffusion of transmitter or by release of gliotransmitters, astrocytes should either hinder or promote the heterosynaptic depression. In the present study we have examined the developmental profile and astrocytic involvement in a transient heterosynaptic depression (tHeSD) in the CA1 region of the rat hippocampal slice preparation. A short stimulus burst (3 impulses at 50 Hz) to one group of synapses elicited a depression of the field EPSP evoked in another group of synapses that amounted to about 25% 0.5 s after the conditioning burst. This tHeSD was associated with an increase in the paired-pulse ratio of about 30%. The tHeSD was not present in slices from rats younger than 10 postnatal days and developed towards the adult magnitude between postnatal days 10 and 20. The tHeSD was totally prevented by the glia-specific toxin fluoroacetate (FAC), by carbenoxolone, a general blocker of connexin-based channels, and by endothelin, an endogenous peptide that has been shown to block astrocytic connexin-based channels. Antagonists to GABA B receptors and group II/III metabotropic glutamate receptors (mGluRs) abolished the tHeSD whereas antagonists to NMDA-and adenosine A1 receptors, and to group I mGluRs, did not affect the tHeSD. These results suggest that the tHeSD relies on GABA B receptors, group II/III mGluRs and on gliotransmitter release from functionally mature astrocytes.

A major challenge in neuroscience is to resolve the connection between gene functionality, neuronal circuits, and behavior. Most, if not all, neuronal circuits of the adult brain contain a glutamatergic component, the nature of which has been difficult to assess because of the vast cellular abundance of glutamate. In this study, we wanted to determine the role of a restricted subpopulation of glutamatergic neurons within the forebrain, the Vglut2-expressing neurons, in neuronal circuitry of higher brain function. Vglut2 expression was selectively deleted in the cortex, hippocampus, and amygdala of preadolescent mice, which resulted in increased locomotor activity, altered social dominance and risk assessment, decreased sensorimotor gating, and impaired long-term spatial memory. Presynaptic VGLUT2-positive terminals were lost in the cortex, striatum, nucleus accumbens, and hippocampus, and a downstream effect on dopamine binding site availability in the striatum was evident. A connection between the induced late-onset, chronic reduction of glutamatergic neurotransmission and dopamine signaling within the circuitry was further substantiated by a partial attenuation of the deficits in sensorimotor gating by the dopamine-stabilizing antipsychotic drug aripiprazole and an increased sensitivity to amphetamine. Somewhat surprisingly, given the restricted expression of Vglut2 in regions responsible for higher brain function, our analyses show that VGLUT2-mediated neurotransmission is required for certain aspects of cognitive, emotional, and social behavior. The present study provides support for the existence of a neurocircuitry that connects changes in VGLUT2-mediated neurotransmission to alterations in the dopaminergic system with schizophrenia-like behavioral deficits as a major outcome.

Optogenetics is one of the most powerful tools in neuroscience, allowing for selective control of specific neuronal populations in the brain of experimental animals, including mammals. We report, for the first time, the application of optogenetic tools to human brain tissue providing a proof-of-concept for the use of optogenetics in neuromodulation of human cortical and hippocampal neurons as a possible tool to explore network mechanisms and develop future therapeutic strategies.

Development of novel disease-modifying treatment strategies for neurological disorders, which at present have no cure, represents a major challenge for today's neurology. Translation of findings from animal models to humans represents an unresolved gap in most of the preclinical studies. Gene therapy is an evolving innovative approach that may prove useful for clinical applications. In animal models of temporal lobe epilepsy (TLE), gene therapy treatments based on viral vectors encoding NPY or galanin have been shown to effectively suppress seizures. However, how this translates to human TLE remains unknown. A unique possibility to validate these animal studies is provided by a surgical therapeutic approach, whereby resected epileptic tissue from temporal lobes of pharmacoresistant patients are available for neurophysiological studies in vitro. To test whether NPY and galanin have antiepileptic actions in human epileptic tissue as well, we applied these neuropeptides directly to human hippocampal slices in vitro. NPY strongly decreased stimulation-induced EPSPs in dentate gyrus and CA1 (up to 30 and 55%, respectively) via Y2 receptors, while galanin had no significant effect. Receptor autoradiographic binding revealed the presence of both NPY and galanin receptors, while functional receptor binding was only detected for NPY, suggesting that galanin receptor signaling may be impaired. These results underline the importance of validating findings from animal studies in human brain tissue, and advocate for NPY as a more appropriate candidate than galanin for future gene therapy trials in pharmacoresistant TLE patients.

Many neurons typically fire action potentials in brief, high-frequency bursts with specific consequences for their synaptic output. Here we have examined short-term plasticity engaged during burst activation using electrophysiological recordings in acute rat hippocampal slices. We show that CA3-CA1 glutamate synapses exhibit a prominent depression of presynaptic release probability for ϳ1 s after such a burst. This postburst depression exhibits a distinct cooperativity threshold, is abolished by inhibiting astrocyte metabolism and astrocyte calcium signaling, and is not operational in the developing hippocampus. Our results suggest that astrocytes are actively involved in short-term synaptic depression, shaping synaptic activity during behaviorally relevant neural activity.