An Input-Specific Orphan Receptor GPR158-HSPG Interaction Organizes Hippocampal Mossy Fiber-CA3 Synapses

Abstract

Summary Pyramidal neuron dendrites integrate synaptic input from multiple partners. Different inputs converging on the same dendrite have distinct structural and functional features, but the molecular mechanisms organizing input-specific properties are poorly understood. We identify the orphan receptor GPR158 as a binding partner for the heparan sulfate proteoglycan (HSPG) glypican 4 (GPC4). GPC4 is enriched on hippocampal granule cell axons (mossy fibers), whereas postsynaptic GPR158 is restricted to the proximal segment of CA3 apical dendrites receiving mossy fiber input. GPR158-induced presynaptic differentiation in contacting axons requires cell-surface GPC4 and the co-receptor LAR. Loss of GPR158 increases mossy fiber synapse density, but disrupts bouton morphology, impairs ultrastructural organization of active zone and postsynaptic density, and reduces synaptic strength of this connection, while adjacent inputs on the same dendrite are unaffected. Our work identifies an input-specific HSPG-GPR158 interaction that selectively organizes synaptic architecture and function of developing mossy fiber-CA3 synapses in the hippocampus.

Gpr158 deficiency impacts hippocampal CA1 neuronal excitability, dendritic architecture, and affects spatial learning

“…Basal synaptic transmission onto CA1 pyramidal cells appears unaffected in Gpr158 KO hippocampus, with no notable changes in either spontaneous excitatory or inhibitory frequency and amplitude observed, in line with recent observations for evoked IPSCs (Ostrovskaya et al, 2018). This is in contrast the reductions observed in sEPSC frequency and amplitude in Gpr158 KO CA3 (Condomitti et al, 2018). Along with the reductions in evoked AMPA and NMDA CA3 currents (Condomitti et al, 2018) as well as the reduced SC mediated responses we observe, it is conceivable that when the network is further challenged, or when miniature release is assessed, such changes may become apparent in CA1 as well.…”

“…Although not yet demonstrated, LTP deficits in the CA1 region akin to those described in CA3 (Condomitti et al, 2018) are likely -as discussed below, and could support deficits in spatial memory acquisition.…”

“…regions (Florian and Roullet, 2004), in which Gpr158 is expressed (Condomitti et al, 2018;Khrimian et al, 2017). Theta frequency coupling between CA3 and CA1 is enhanced during MWM learning, when there is a clear improvement in task performance (Hernández-Pérez et al, 2016).…”

“…In the SC to CA1 network, brain-derived neurotrophic factor (BDNF) is required for the induction and maintenance of LTP brought about by repeated dopamine stimulation in apical but not in basal dendrites (Navakkode et al, 2012), and hippocampal BDNF levels in Gpr158 KO are found reduced (Khrimian et al, 2017). To date, impaired PPR and LTP in Gpr158 KOs has been reported for the MF to CA3 pathway (Condomitti et al, 2018;Khrimian et al, 2017), but LTP has not been investigated for the CA3 to CA1 pathway. Although we report normal PPR for this pathway, given the robust reduction in CA3 to CA1 stimulation and deficient dendritic architecture we observe, along with reduced hippocampal BDNF levels (Khrimian et al, 2017), it is safe to speculate that CA3 to CA1 LTP will likely be impaired in Gpr158 KO as well, driving impairments in spatial memory.…”

“…Recent work has begun shedding light on the precise function of Gpr158 (Condomitti et al, 2018;Khrimian et al, 2017;Orlandi et al, 2012;Sutton et al, 2018). Gpr158 overexpression in mouse medial PFC (mPFC) increases helplessness, illustrated by increased immobility in a tail-suspension (TST) and forced-swim tests (FST) (Sutton et al, 2018).…”