Gpr158 Deficiency Impacts Hippocampal CA1 Neuronal Excitability, Dendritic Architecture, and Affects Spatial Learning

Abstract

G-protein-coupled receptor 158 (Gpr158) is highly expressed in striatum, hippocampus and prefrontal cortex. It gained attention as it was implicated in physiological responses to stress and depression. Recently, Gpr158 has been shown to act as a pathway-specific synaptic organizer in the hippocampus, required for proper mossy fiber-CA3 neurocircuitry establishment, structure, and function. Although rodent Gpr158 expression is highest in CA3, considerable expression occurs in CA1 especially after the first postnatal month. Here, we combined hippocampal-dependent behavioral paradigms with subsequent electrophysiological and morphological analyses from the same group of mice to assess the effects of Gpr158 deficiency on CA1 physiology and function. We demonstrate deficits in spatial memory acquisition and retrieval in the Morris water maze paradigm, along with deficits in the acquisition of extinction memory in the passive avoidance test in Gpr158 KO mice. Electrophysiological recordings from CA1 pyramidal neurons revealed normal basal excitatory and inhibitory synaptic transmission, however, Schaffer collateral stimulation yielded dramatically reduced post-synaptic currents. Interestingly, intrinsic excitability of CA1 pyramidals was found increased, potentially acting as a compensatory mechanism to the reductions in Schaffer collateral-mediated drive. Both ex vivo and in vitro, neurons deficient for or with lowered levels of Gpr158 exhibited robust reductions in dendritic architecture and complexity, i.e., reduced length, surface, bifurcations, and branching. This effect was localized in the apical but not basal dendrites of adult CA1 pyramidals, indicative of compartment-specific alterations. A significant positive correlation between spatial memory acquisition and extent of complexity of CA1 pyramidals was found. Taken together, we provide first evidence of significant disruptions in hippocampal CA1 neuronal dendritic architecture and physiology, driven by Gpr158 deficiency. Importantly, the hippocampal neuronal morphology deficits appear to support the impairments in spatial memory acquisition observed in Gpr158 KO mice.

Identification of KIAA0513 and Other Hub Genes Associated With Alzheimer Disease Using Weighted Gene Coexpression Network Analysis

“…GABRD encodes the delta subunit of γ-aminobutyric acid type A (GABA-A) receptor, named GABRD, which was necessary for synaptic plasticity in the hippocampi of mouse models (Whissell et al, 2016). GPR158 encodes G protein-coupled receptor 158 (GPR158), which was found to be important in synaptic modulation, especially in the hippocampus (Khrimian et al, 2017;Condomitti et al, 2018;Sutton et al, 2018;Cetereisi et al, 2019). KIAA0513 encodes the protein KIAA0513, which was assumed to participate in neuroplasticity and apoptosis (Lauriat et al, 2006).…”

Orphan G Protein Coupled Receptors in Affective Disorders

“…Finally, quantitative proteomics showed that GPR158 is particularly enriched in the PFC, where it is by far the most expressed oGPCR [92]. In the rest of the brain, GPR158 is also highly expressed in the striatum, amygdala, cerebellum, and hippocampus [93,94,203,204,208].…”

“…Male rats, adult, hypothalamus, microarray, ↓ mRNA by fluoxetine [87]. EPM, male GPR88 KO vs. WT mice, 8-15 week-old, ↑ time in open arms [88], [89], [90] MBT, male GPR88 KO vs. WT mice, 8-15 week-old, ↓ marble buried [88], [89], [90] NSFT, male GPR88 KO vs. WT mice, 8-10 week-old, ↓ latency to feed [88] LDT, male GPR88 KO vs. WT mice, 9-15 week-old, ↑ time in lit box [89] LDT, male A2AR-GPR88 KO vs. GPR88flx/flx mice, 9-15 week-old, ↑ time in lit box [89] EPM, male A2AR-GPR88 KO vs. GPR88flx/flx mice, 9-15 week-old, ↑ time in open arms [89] MBT, male A2AR-GPR88 KO vs. GPR88flx/flx mice, 9-15 week-old, ↓ marble buried [89], [90] NFST, male A2AR-GPR88 KO vs. GPR88flx/flx mice, 9-15 week-old, ↔ latency to feed [89] MBT, male D1R-GPR88 KO vs. GPR88flx/flx mice, 9-15 week-old, ↔ marble buried [90] FST, male GPR88 KD in DMS vs. CNT rats, 7 week-old, ↓ immobility [91] SPT, male GPR88 KD in DMS vs. CNT rats, 7 week-old, ↔ ratio [91] [92] Primary cortical neurons, WB, ↑ levels by chronic corticosterone [92] TST, male GPR158 KO vs. WT mice, 2-4 month-old, ↓ immobility, rescued by viral GPR158 OE in mPFC [92] TST, female GPR158 KO vs. WT mice, 2-4 month-old, ↓ immobility [92] TST, male GPR158 OE in mPFC vs. control mice, 2-4 month-old, ↑ immobility [92] FST, male GPR158 KO vs. WT mice, 2-4 month-old, ↓ immobility, rescued by viral GPR158 OE in mPFC [92] FST, female GPR158 KO vs. WT mice, 2-4 month-old, ↓ immobility [92] FST, male GPR158 OE in mPFC vs. control mice, 2-4 month-old, ↑ immobility [92] EPM, male GPR158 KO vs. WT [92] MBT, male GPR158 KO vs. WT mice, 2-4 month-old, ↓ marble buried [92] MBT, female GPR158 KO vs. WT mice, 2-4 month-old, ↓ marble buried [92] LDT, female GPR158 KO vs. WT mice, 3 month-old, ↓ time in lit box [93] OFT, female GPR158 KO vs. WT mice, 3 month-old, ↓ time in center [93] OFT, male GPR158 KO vs. WT mice, 8-12 week-old, ↔ time in center [94] TST after UCMS, GPR1...…”

Bone-Derived Modulators That Regulate Brain Function: Emerging Therapeutic Targets for Neurological Disorders

“…Further research showed that OCN could reduce the loss of tyrosine hydroxylase in the nigrostriatal system and regulate astrocytic and microglial functions (Guo et al, 2018). Gpr158 is the only central receptor of OCN found in the brain, but whether OCN can exert its neuroprotective efficacy in a PD rat model by binding to Gpr158 is still unknown (Khrimian et al, 2017;Cetereisi et al, 2019). Kim et al (2016) showed that LCN2 expression was significantly elevated in the substantia nigra of PD patients, and there was a negative correlation between LCN2 levels and dopaminergic neurons.…”

“…Further research showed that OCN could reduce the loss of tyrosine hydroxylase in the nigrostriatal system and regulate astrocytic and microglial functions ( Guo et al, 2018 ). Gpr158 is the only central receptor of OCN found in the brain, but whether OCN can exert its neuroprotective efficacy in a PD rat model by binding to Gpr158 is still unknown ( Khrimian et al, 2017 ; Cetereisi et al, 2019 ).…”