SorCS2 is required for BDNF-dependent plasticity in the hippocampus.

SorCS2 is a member of the Vps10p-domain receptor gene family receptors with critical roles in the control of neuronal viability and function. Several genetic studies have suggested SORCS2 to confer risk of bipolar disorder, schizophrenia and attention deficit-hyperactivity disorder. Here we report that hippocampal N-methyl-d-aspartate receptor-dependent synaptic plasticity is eliminated in SorCS2-deficient mice. This defect was traced to the ability of SorCS2 to form complexes with the neurotrophin receptor p75NTR, required for pro-brain-derived neurotrophic factor (BDNF) to induce long-term depression, and with the BDNF receptor tyrosine kinase TrkB to elicit long-term potentiation. Although the interaction with p75NTR was static, SorCS2 bound to TrkB in an activity-dependent manner to facilitate its translocation to postsynaptic densities for synaptic tagging and maintenance of synaptic potentiation. Neurons lacking SorCS2 failed to respond to BDNF by TrkB autophosphorylation, and activation of downstream signaling cascades, impacting neurite outgrowth and spine formation. Accordingly, Sorcs2-/- mice displayed impaired formation of long-term memory, increased risk taking and stimulus seeking behavior, enhanced susceptibility to stress and impaired prepulse inhibition. Our results identify SorCS2 as an indispensable coreceptor for p75NTR and TrkB in hippocampal neurons and suggest SORCS2 as the link between proBDNF/BDNF signaling and mental disorders.

A novel dualistic profile of an allosteric AMPA receptor modulator identified through studies on recombinant receptors, mouse hippocampal synapses and crystal structures.

Positive allosteric modulators (PAMs) of 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptors receive increasing interest as therapeutic drugs and have long served as important experimental tools in the study of the molecular mechanisms underlying glutamate-mediated neurotransmission. The aim of this study was to investigate functional and structural aspects of a novel analog of the AMPA receptor PAM cyclothiazide (CTZ) on recombinant and native glutamate receptors. We expressed rat GluA4flip and flop in Xenopus oocytes and characterized NS1376 and CTZ under two-electrode voltage-clamp. The dose-response analyses revealed dual effects of NS1376. The modulator induced 30-fold and 42-fold reductions in glutamate potency and increased the glutamate efficacy by 3.2-fold and 5.3-fold at GluA4flip and GluA4flop, respectively. Rapid application of glutamate to excised outside-out patches showed that NS1376 markedly attenuated desensitization, supporting the increased efficacy observed in the oocytes. Furthermore, when applied to acutely isolated mouse brain slices, NS1376 reduced the field excitatory postsynaptic potentials (fEPSPs) in the hippocampus to 51.6 ± 4.3% of baseline, likely as a consequence of reduced glutamate potency. However, the modulator displayed no effects on a sub-maximal long-term potentiation (LTP) protocol. We confirmed that CTZ increases presynaptic transmitter release, a property which was not shared by NS1376. Finally, we obtained detailed molecular information through X-ray structures, docking and molecular dynamics, which revealed that NS1376 interacts at the dimer interface of the ligand-binding domain in a manner overall similar to CTZ. NS1376 reveals that minor structural changes in CTZ can result in an altered modulatory profile, both enhancing agonist efficacy while markedly reducing agonist potency. These unique properties add new aspects to the complexity of allosteric modulations in neuronal systems.

Kinetic analysis of evoked IPSCs discloses mechanism of antagonism of synaptic GABAA receptors by picrotoxin.

BACKGROUND AND PURPOSE: Although picrotoxin is a well-established antagonist of GABA(A) receptors, detailed studies of its action on inhibitory synaptic transmission have not previously been made. EXPERIMENTAL APPROACH: Electrophysiological techniques were used to study the action of picrotoxin on inhibitory postsynaptic currents (IPSCs) evoked in hippocampal neurones, in culture and slice preparations prepared from Wistar rat embryos and juveniles, respectively. KEY RESULTS: Picrotoxin gradually reduced the amplitude of GABA(A) receptor-mediated eIPSCs in a concentration-dependent manner. This was accompanied by a marked acceleration of the eIPSC decay kinetics, which, in contrast to the effect on amplitude, developed immediately and was completely reversed on washing. The decaying phase of the IPSC could be resolved into two components; 30 microM picrotoxin reduced tau(fast) by 34% and increased its relative amplitude, while tau(slow) was reduced by 38%, and its relative amplitude decreased. The area under the decaying phase of the normalized eIPSC showed an immediate reduction by 36% in 30 microM picrotoxin. With increasing concentrations of picrotoxin, this normalized area converged towards 55% of the control, indicating that the rate of relaxation and block has a finite maximum. This implies that picrotoxin does not act by a pore-occluding mechanism (open-channel blocking), and suggests allosteric stabilization of desensitized receptor states as a more likely alternative. This was corroborated by modelling, based on two established microscopic GABA(A) receptor transition schemes. CONCLUSIONS AND IMPLICATIONS: Although the identity of the stabilized state has not been determined unequivocally, picrotoxin effectively traps synaptic GABA(A) receptors in a desensitized state.