Neuropilin 2 signaling mediates corticostriatal transmission, spine maintenance, and goal-directed learning in mice

Abstract

The striatum represents the main input structure of the basal ganglia, receiving massive excitatory input from the cortex and the thalamus. The development and maintenance of cortical input to the striatum is crucial for all striatal function including many forms of sensorimotor integration, learning and action control. The molecular mechanisms regulating the development and maintenance of corticostriatal synaptic transmission are unclear. Here we show that the guidance cue, Semaphorin 3F and its receptor Neuropilin 2 (Nrp2), influence dendritic spine maintenance, corticostriatal short-term plasticity, and learning in adult male and female mice. We found that Nrp2 is enriched in adult layer V pyramidal neurons, corticostriatal terminals, and in developing and adult striatal spiny projection neurons (SPNs). Loss of Nrp2 increases SPN excitability and spine number, reduces short-term facilitation at corticostriatal synapses, and impairs goal-directed learning in an instrumental task. Acute deletion of Nrp2 selectively in adult layer V cortical neurons produces a similar increase in the number of dendritic spines and presynaptic modifications at the corticostriatal synapse in the Nrp2 -/mouse, but does not affect the intrinsic excitability of SPNs. Furthermore conditional loss of Nrp2 impairs sensorimotor learning on the accelerating rotarod without affecting goal-directed instrumental learning. Collectively, our results identify Nrp2 signaling as essential for the development and maintenance of the corticostriatal pathway and may shed novel insights on neurodevelopmental disorders linked to the corticostriatal pathway and semaphorin signaling. Significance StatementThe corticostriatal pathway controls sensorimotor, learning and action control behaviors and its dysregulation is linked to neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here we demonstrate that neuropilin 2 (Nrp2), a receptor for the axon-guidance cue semaphorin 3F, has important and previously unappreciated functions in the development and adult maintenance of dendritic spines on striatal spiny projection neurons (SPNs), corticostriatal short-term plasticity, intrinsic physiological properties of SPNs and learning in mice. Our findings, coupled with Nrp2's association with ASD in human populations, suggest that Nrp2 may play an important role in ASD pathophysiology. Overall, our work demonstrates Nrp2 as a key regulator of corticostriatal development, maintenance and function, and may lead to better understanding of neurodevelopmental disease mechanisms.

Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning

“…To investigate this, we measured the paired pulse ratio (PPR) of AMPAR currents evoked by two electrical stimuli delivered 50 ms apart. The stimulating electrode was placed in or just above the corpus callosum to preferentially activate cortical inputs (Ding et al, 2008;Assous et al, 2019). We found a significant decrease in PPR in dSPN-Tsc1 KO cells compared to WT, consistent with increased presynaptic release probability of cortical inputs onto dSPNs (Figure 4L).…”

The HDAC inhibitor CI-994 acts as a molecular memory aid by facilitating synaptic and intra-cellular communication after learning

“…5C-D), we found that HDACi paired with rotarod training selectively increased striatal PPF (two-way ANOVA, F(3,192) = 12.217, P = 2.37e-07) (Supplemental Fig. 5E-F), which is known to underlie motor learning in the striatum (29). In addition, there were no major differences in I/O in the striatum or the hippocampus (Supplemental Fig.…”

“…The brain region-specific electrophysiological effects likely occur because the HDACi treatment reinforces behaviorally relevant cellular pathways per brain area. When paired with CFC, HDACi specifically enhances hippocampal LTP, which is known to underlie contextual fear learning (66)(67)(68)(69); whereas when paired with rotarod training, HDACi enhances cortico-striatal PPF, which is known to underlie motor learning (29,70,71). This specialization is further supported by the differential transcriptional programs activated in the hippocampus and striatum.…”

Induced pluripotent stem cell-derived astrocytes from patients with schizophrenia exhibit an inflammatory phenotype that affects vascularization

“…Of note, several of these proteins are involved in vascular and neural development 61, 62 . Neuropilin acts as a co-receptor in both pathways during axon morphogenesis 63 and angiogenesis (Gelfand et al, 2014), as well as in association with semaphorin and VEGF. Here, we observed that all experimental groups of hiPSC-derived astrocyte-conditioned media increase angiogenesis in chick embryos, supporting the supposition that astrocytes are an important source of angiogenic factors in the CNS 64 .…”