Acute cannabinoids impair working memory through astroglial CB1 receptor modulation of hippocampal LTD.

Impairment of working memory is one of the most important deleterious effects of marijuana intoxication in humans, but its underlying mechanisms are presently unknown. Here, we demonstrate that the impairment of spatial working memory (SWM) and in vivo long-term depression (LTD) of synaptic strength at hippocampal CA3-CA1 synapses, induced by an acute exposure of exogenous cannabinoids, is fully abolished in conditional mutant mice lacking type-1 cannabinoid receptors (CB(1)R) in brain astroglial cells but is conserved in mice lacking CB(1)R in glutamatergic or GABAergic neurons. Blockade of neuronal glutamate N-methyl-D-aspartate receptors (NMDAR) and of synaptic trafficking of glutamate α-amino-3-hydroxy-5-methyl-isoxazole propionic acid receptors (AMPAR) also abolishes cannabinoid effects on SWM and LTD induction and expression. We conclude that the impairment of working memory by marijuana and cannabinoids is due to the activation of astroglial CB(1)R and is associated with astroglia-dependent hippocampal LTD in vivo.

Early inflammation dysregulates neuronal circuit formation in vivo via upregulation of IL-1ß.

Neuro-immune interaction during development is strongly implicated in the pathogenesis of neurodevelopmental disorders, but the mechanisms that cause neuronal circuit dysregulation are not well understood. We performed in vivo imaging of the developing retinotectal system in the larval zebrafish to characterize the effects of immune system activation on refinement of an archetypal sensory processing circuit. Acute inflammatory insult induced hyper-dynamic remodeling of developing retinal axons in larval fish and increased axon arbor elaboration over days. Using calcium imaging in GCaMP6s transgenic fish we showed that these morphological changes were accompanied by a shift toward decreased visual acuity in tectal cells. This finding was supported by poorer performance in a visually guided behavioral task. We further found that the pro-inflammatory cytokine, interleukin-1ß (IL-1ß) is upregulated by the inflammatory insult, and that down-regulation of IL-1ß abrogated the effects of inflammation on axonal dynamics and growth. Moreover, baseline branching of the RGC arbors in IL-1ß morphant animals was significantly different from that in control larvae, and their performance in a predation assay was impaired, indicating a role for this cytokine in normal neuronal development. This work establishes a simple and powerful non-mammalian model of developmental immune activation and demonstrates a role for IL-1ß in mediating the pathological effects of inflammation on neuronal circuit development.SIGNIFICANCE STATEMENTMaternal immune activation (MIA) can increase the risk of neurodevelopmental disorders in offspring, however the mechanisms involved are not fully understood. Using a non-mammalian vertebrate model of developmental immune activation, we show that even brief activation of inflammatory pathways has immediate and long-term effects on the arborization of axons, and that these morphological changes have functional and behavioral consequences. Finally, we show that the pro-inflammatory cytokine IL-1ß plays an essential role in both the effects of inflammation on circuit formation and normal axonal development. Our data add to a growing body of evidence supporting epidemiological studies linking immune activation to neurodevelopmental disorders, and help shed light on the molecular and cellular processes that contribute to the etiology of these disorders.

Postsynaptic and Presynaptic NMDARs Have Distinct Roles in Visual Circuit Development.

To study contributions of N-methyl-D-aspartate receptors (NMDARs) in presynaptic and postsynaptic neurons of the developing visual system, we microinject antisense Morpholino oligonucleotide (MO) against GluN1 into one cell of two-cell-stage Xenopus laevis embryos. The resulting bilateral segregation of MO induces postsynaptic NMDAR (postNMDAR) knockdown in tectal neurons on one side and presynaptic NMDAR (preNMDAR) knockdown in ganglion cells projecting to the other side. PostNMDAR knockdown reduces evoked NMDAR- and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated retinotectal currents. Although the frequency of spontaneous synaptic events is increased, the probability of evoked release is reduced. PreNMDAR knockdown results in larger evoked and unitary synaptic responses. Structurally, postNMDAR and preNMDAR knockdown produce complementary effects. Axonal arbor complexity is reduced by preNMDAR-MO and increased by postNMDAR-MO, whereas tectal dendritic arbors exhibit the inverse. The current study illustrates distinct roles for pre- and postNMDARs in circuit development and reveals extensive transsynaptic regulation of form and function.

Formula for Unsilencing Plasticity: Spike with GABA.

A complication for developmental plasticity mechanisms like spike-timing-dependent plasticity (STDP) is that immature postsynaptic neurons may lack sufficient input to fire action potentials. In this issue, van Rheede et al. (2015) report an activity-dependent mechanism that converts non-spiking cells into spiking neurons, priming them for further plasticity.