Eroglu, C. | bioRxiv Science

bioRxiv2019

Thrombospondin-1 Promotes Circuit-Specific Synapse Formation via β1-Integrin

Glial cells regulate synaptic connectivity during development, but whether they selectively instruct the formation of specific synaptic circuits is not known. Here we show that the major perisynaptic glia of the retina, the Muller glia (MG), control the proper establishment of the direction-selective (DS) circuit by a synaptogenic protein, Thrombospondin 1 (TSP1). We found that TSP1 promotes excitatory synapse formation specifically in on-off Direction-Selective retinal Ganglion Cells (ooDSGCs). Lack of TSP1 leads to reduced synapse formation within the inner plexiform sublayers containing DS-circuit, resulting in deficits of ooDSGC function. Even though pan-TSP receptor, 2{delta}-1, interaction is required for TSP1-induced synapse formation, the ooDSGC-subtype specificity of TSP1 is conferred by a second neuronal TSP1 receptor, {beta}1-Integrin. Furthermore, conditional deletion of {beta}1-Integrin in ooDSGCs results in diminished excitatory synapse formation without disturbing laminar organization showing that MG-secreted TSP1 controls circuit-specific synapse formation via {beta}1-Integrin.

neuroscience↗

bioRxiv2019

Developmental onset of enduring long-term potentiation in mouse hippocampus

Analysis of long-term potentiation (LTP) provides a powerful window into cellular mechanisms of learning and memory. Prior work shows late LTP (L-LTP), lasting >3 hours, occurs abruptly at postnatal day 12 (P12) in rat hippocampus. The goal here was to determine the developmental profile of synaptic plasticity leading to L-LTP in the mouse hippocampus. Two mouse strains and two mutations known to affect synaptic plasticity were chosen: C57BL/6 and Fmr1-/y on the C57BL/6 background, and 129SVE and Hevin-/- (Sparcl1-/-) on the 129SVE background. Like rats, hippocampal slices from all of the mice showed test pulse-induced depression early during development that was gradually resolved with maturation by 5 weeks. All the mouse strains showed a gradual progression between P10-P35 in the expression of short-term potentiation (STP), lasting [≤] one hour. In the 129SVE mice, L-LTP onset (>25% of slices) occurred by 3 weeks, reliable L-LTP (>50% slices) was achieved by 4 weeks, and Hevin-/- advanced this profile by one week. In the C57BL/6 mice, L-LTP onset occurred significantly later, over 3-4 weeks, and reliability was not achieved until 5 weeks. Although some of the Fmr1-/y mice showed L-LTP before 3 weeks, reliable L-LTP also was not achieved until 5 weeks. Two bouts of TBS separated by [≥]90 minutes advanced the onset age of L-LTP in rats from P12 to P10. In contrast, L-LTP onset was not advanced in any of the mouse genotypes by multiple bouts of TBS at 90 or 180 minute intervals. These findings show important species differences in the onset of STP and L-LTP, which occur at the same age in rats but are sequentially acquired in mice. SIGNIFICANCE STATEMENTLong-term potentiation (LTP) is a cellular mechanism of learning and memory. Knowing the developmental profile for LTP provides a basis for investigating developmental abnormalities leading to intellectual disabilities and other neurodevelopmental disorders. Here we explore the developmental profile of LTP onset in two wild type mouse strains, C57BL/6 and 129SVE, together with Fmr1-/y and Hevin-/- (Sparcl1-/-) mutations that produce abnormalities in synaptic structure, plasticity, and development. Our data provide a foundation for future investigations into connections between structural and functional plasticity leading to developmental anomalies in the brain.

neuroscience↗