The sorting receptor SorCS3 is a stronger regulator of glutamate receptor functions compared to GABAergic mechanisms in the hippocampus

Abstract

Correct function of glutamate receptors in the postsynaptic density is crucial to synaptic function and plasticity. SorCS3 (sortilin-related receptor CNS expressed 3) is a sorting receptor which previously has been shown to interact with the key postsynaptic proteins; PSD-95 and PICK1. In this study, we employed electrophysiological analyses of acute brain slices combined with immunohistochemistry to define the role of SorCS3 in hippocampal synapses in CA1 and the dentate gyrus. We analyzed a juvenile (P17-21) and a young adult (P55-65) group of animals from a Sorcs3 knockout mouse model. We show that the basal synaptic transmission is severely affected in SorCS3-deficient neurons in CA1, while only slightly reduced in the dentate gyrus. Specifically, input/output curves of CA1 synapses revealed a 20% reduction of fEPSP (field excitatory postsynaptic potential) slopes at the highest stimulation intensity in knockouts of the juvenile group, which developed to a 33% decrease in young adult animals. These impairments may be a result of changes in the postsynaptic AMPA receptors. Interestingly, repetitive afferent stimulation demonstrated that SorCS3-deficient slices respond with an enhanced synaptic facilitation and reduced synaptic depression. These changes also developed with age. A molecular mechanism underlying this relative increase during repetitive stimulations is compatible with enhanced mobility of postsynaptic AMPA receptors resulting in faster exchange of desensitized receptors in the postsynaptic density. The altered response during repetitive stimulation was characteristic for CA1 but not the dentate gyrus. Immunohistochemical analyses of parvalbumin positive neurons combined with paired-pulse tests of network inhibition and patch-clamp recordings only showed minute inhibitory changes in SorCS3-deficient slices. Our results suggest that SorCS3 serves an important role in the postsynaptic protein network, which is more pronounced in CA1 compared to the dentate gyrus. These data support a role for SorCS3 in controlling proper positioning and mobility of glutamate receptors in the postsynaptic density. © 2016 Wiley Periodicals, Inc.

Multi-trait analysis for genome-wide association study of five psychiatric disorders

“…SORCS3, together with another VPS10p-domain receptor-SORCS1, can control energy balance and orexigenic peptide production by attenuating BDNF signaling 56 . SORCS1 is a stronger regulator of glutamate receptor functions compared with GABAergic signaling, thereby acting as a key regulator of synaptic transmission and plasticity 57 . SORCS3 is also a postsynaptic modulator of synaptic depression and fear extinction, affecting NMDA receptordependent and -independent long-term depression 58 .…”

Detecting Local Genetic Correlations with Scan Statistics

“…SORCS3 (Figure 5B) is highly expressed in the CA1 region of the hippocampus, and is involved in synaptic depression and spatial learning ability 56,57 . It is also known to play an important role in protein networks associated with PICK1, NGF, and PDGF-BB 58,59 which have been implicated in ADHD, ASD, MDD, and SCZ [60][61][62][63] . NTM (Figure 5C) regulates the outgrowth of neurites, and is associated with the formation of excitatory synapses 64,65 .…”

Tbr1 instructs laminar patterning of retinal ganglion cell dendrites

“…Most relevant here, Sorcs3 protein appears to be preferentially localized to neuronal dendrites. In hippocampus, Sorcs3 is present at dendritic spines, where it participates in the modulation of glutamate receptor function 44 – 46 . Similarly, it is concentrated in dendrites of J-RGCs.…”