Adenylyl cyclase I regulates AMPA receptor trafficking during mouse cortical 'barrel' map development

Abstract

Cortical map formation requires the accurate targeting, synaptogenesis, elaboration and refinement of thalamocortical afferents. Here we demonstrate the role of Ca2+/calmodulin-activated type-I adenylyl cyclase (AC1) in regulating the strength of thalamocortical synapses through modulation of AMPA receptor (AMPAR) trafficking using barrelless mice, a mutant without AC1 activity or cortical 'barrel' maps. Barrelless synapses are stuck in an immature state that contains few functional AMPARs that are rarely silent (NMDAR-only). Long-term potentiation (LTP) and long-term depression (LTD) at thalamocortical synapses require postsynaptic protein kinase A (PKA) activity and are difficult to induce in barrelless mice, probably due to an inability to properly regulate synaptic AMPAR trafficking. Consistent with this, both the extent of PKA phosphorylation on AMPAR subunit GluR1 and the expression of surface GluR1 are reduced in barrelless neurons. These results suggest that activity-dependent mechanisms operate through an AC1/PKA signaling pathway to target some synapses for consolidation and others for elimination during barrel map formation.

The cyclic AMP phenotype of fragile X and autism

“…Developmentally, dysregulation of the cAMP cascade is known to impact growth cone motility and the structure of terminal varicosities in Drosophila (Kim and Wu 1996). Cyclic AMP plays an important role in AMPA trafficking (Lu, She et al 2003), cell survival and neurogenesis (Nakagawa, Kim et al 2002), neural induction (Otte, van Run et al 1989), neurite formation, and synaptogenesis (Takuro Tojima 2003). Cyclic AMP also regulates spine density by gating brain derived neurotrophic factor (BDNF) signaling, a neurotrophin implicated in dendrite formation (Ji, Pang et al 2005).…”

Conditional Dnmt1 deletion in dorsal forebrain disrupts development of somatosensory barrel cortex and thalamocortical long-term potentiation

“…NMDA receptor blockade (Crair and Malenka, 2005), and PKA RIIβ deletion both prevent thalamocortical LTP during early development (Watson et al, 2006) but cortical deletion of the critical NMDA receptor subunit NR1 (Iwasato et al, 2000) and deletion of PKA RIIβ (Watson et al, 2006;Inan et al, 2006), while blurring barrel boundaries, do not completely disrupt formation of somatosensory cortical barrels. Finally, while studies have suggested the importance of GluR1 trafficking for thalamocortical long-term potentiation (Lu et al, 2003), barrels form normally in GluR1 KO mice (Watson et al, 2006), again suggesting that thalamocortical LTP may not be essential for the development of somatosensory cortical barrels. This would suggest that the lack of thalamocortical LTP is unlikely to be the sole direct cause of the lack of development of somatosensory cortical barrels in Emx1-cre;Dnmt1 mutants.…”

“…Considerable controversy exists on whether thalamocortical long-term potentiation is essential for barrel formation. Barrel formation and thalamocortical plasticity are both disrupted by adenylyl cyclase I deletion (Abdel Majid et al, 1998;Lu et al, 2003). NMDA receptor blockade (Crair and Malenka, 2005), and PKA RIIβ deletion both prevent thalamocortical LTP during early development (Watson et al, 2006) but cortical deletion of the critical NMDA receptor subunit NR1 (Iwasato et al, 2000) and deletion of PKA RIIβ (Watson et al, 2006;Inan et al, 2006), while blurring barrel boundaries, do not completely disrupt formation of somatosensory cortical barrels.…”

“…In a number of mouse strains where periphery-related patterns do not develop in barrel cortex, thalamocortical LTP has been shown to be deficient (Iwasato et al, 2003;Lu et al, 2003). This has prompted investigators to conclude that strengthening of thalamocortical synapses through LTP-like phenomena during early development may be essential for development of periphery-related patterns in barrel cortex (Lu et al, 2003;Inan et al, 2006).…”

“…This has prompted investigators to conclude that strengthening of thalamocortical synapses through LTP-like phenomena during early development may be essential for development of periphery-related patterns in barrel cortex (Lu et al, 2003;Inan et al, 2006). This enticed us to determine whether thalamocortical long-term potentiation can be elicited in Emx1-cre;Dnmt1 mutant cortex.…”