Cortico-basal ganglia-thalamocortical loops are largely conceived as parallel circuits that process limbic, associative, and sensorimotor information separately. Whether and how these functionally distinct loops interact remains unclear. Combining genetic and viral approaches, we systemically mapped the limbic and motor cortico-basal ganglia-thalamocortical loops in rodents. Despite largely closed loops within each functional domain, we discovered a unidirectional influence of the limbic over the motor loop via ventral striatum-substantia nigra (SNr)-motor thalamus circuitry. Slice electrophysiology verifies that the projection from ventral striatum functionally inhibits nigro-thalamic SNr neurons. In vivo optogenetic stimulation of ventral or dorsolateral striatum to SNr pathway modulates activity in medial prefrontal cortex (mPFC) and motor cortex (M1), respectively. However, whereas the dorsolateral striatum-SNr pathway exerts little impact on mPFC, activation of the ventral striatum-SNr pathway effectively alters M1 activity. These results demonstrate an open cortico-basal ganglia loop whereby limbic information could modulate motor output through ventral striatum control of M1.

2+-dependent signaling and synaptic plasticity. Previous studies have suggested that the synaptic trafficking of NMDAR subtypes is differentially regulated, but the precise molecular mechanism is not yet clear. In this study, we demonstrated that Bip, an endoplasmic reticulum (ER) chaperone, selectively interacted with GluN2A and mediated the neuronal activity-induced assembly and synaptic incorporation of the GluN2A-containing NMDAR from dendritic ER. Furthermore, the GluN2A-specific synaptic trafficking was effectively disrupted by peptides interrupting the interaction between Bip and GluN2A. Interestingly, fear conditioning in mice was disrupted by intraperitoneal injection of the interfering peptide before training. In summary, we have uncovered a novel mechanism for the activity-dependent supply of synaptic GluN2A-containing NMDARs, and demonstrated its relevance to memory formation.

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Long term synaptic plasticity, such as long term potentiation (LTP), has been widely accepted as a cellular mechanism underlying memory. Recently, it has been unraveled that Shp2 plays a role in synaptic plasticity and memory in Drosophila and mice, revealing significant and conserved effects of Shp2 in cognitive function. However, the exact mechanism underlying this function of Shp2 in synaptic plasticity and memory still remains elusive. Here, we examine the regulation of Shp2 in hippocampal LTP and contextual fear conditioning. We find that Shp2 is rapidly recruited into spines after LTP induction. Furthermore, the phosphorylation level of Shp2 at Tyr-542 is elevated after LTP stimuli either in cultured hippocampal neurons or acute slices. Notably, contextual fear conditioning also regulates the phosphorylation level of Shp2 at Tyr-542, suggesting fine-tuned regulation of Shp2 in LTP and memory formation. By using a Shp2-specific inhibitor and adeno-associated virus-Cre mediated Shp2 knock-out in cultured neurons, we provide evidence that the phosphatase activity of Shp2 is critical for activity-dependent AMPA receptor surface trafficking. Collectively, our results have revealed a regulatory mechanism of Shp2 underlying LTP and memory, broadening our understanding of Shp2 in cognitive function.

Src homolog domain-containing phosphatase 2 (Shp2) signals a variety of cellular and physiological functions including learning and memory. Dysregulation of ERK signaling is known to be responsible for the cognitive deficits associated with gain-of-function mutated Shp2 mimicking Noonan syndrome. However, here, we report that CaMKIIα-cre induced knockout (CaSKO) of Shp2 in hippocampal pyramidal neurons resulted in increased Src activity, upregulated phosphorylation of N-methyl-D-aspartate receptors (NMDARs) at Y1325 of GluN2A and at Y1472 of GluN2B, disrupted the balance of synaptic transmission, and impaired long-term potentiation and remote contextual fear memory. Administration of PP2, a specific Src family kinase inhibitor, reversed the tyrosine phosphorylation of NMDARs, restored basal synaptic transmission, and rescued the contextual fear memory deficit in CaSKO mice without altering the phospho-ERK level. Taken together, our results reveal a novel role of Shp2 in NMDAR-dependent synaptic function and fear memory via the Src signaling pathway rather than the ERK pathway, and suggest a complicated mechanism for Shp2-associated cognitive deficits.