NMDA-type glutamate receptors play a critical role in the activity-dependent development and structural remodeling of dendritic arbors and spines. However, the molecular mechanisms that link NMDA receptor activation to changes in dendritic morphology remain unclear. We report that the Rac1-GEF Tiam1 is present in dendrites and spines and is required for their development. Tiam1 interacts with the NMDA receptor and is phosphorylated in a calcium-dependent manner in response to NMDA receptor stimulation. Blockade of Tiam1 function with RNAi and dominant interfering mutants of Tiam1 suggests that Tiam1 mediates effects of the NMDA receptor on dendritic development by inducing Rac1-dependent actin remodeling and protein synthesis. Taken together, these findings define a molecular mechanism by which NMDA receptor signaling controls the growth and morphology of dendritic arbors and spines.

The development of dendritic spines is thought to be crucial for synaptic plasticity.Dendritic spines are retracted upon EphA4 activation, but the mechanisms that control this process are not well understood. Here we report an important role of Cdk5 in EphA4-dependent spine retraction. We find that blockade of Cdk5 activity inhibits ephrin-A1-triggered spine retraction and reduction of mEPSC frequency at hippocampal synapses.Activation of EphA4 results in the recruitment of Cdk5 to EphA4, leading to the tyrosine phosphorylation and activation of Cdk5. EphA4 and Cdk5 then enhance the activation of ephexin1, a GEF that regulates RhoA activation. We show that the association between EphA4 and ephexin1 is significantly reduced in Cdk5 -/-brains and that Cdk5-dependent phosphorylation of ephexin1 is required for ephrin-A1-mediated regulation of spine density.These findings suggest that ephrin-A1 promotes EphA4-dependent spine retraction through the activation of Cdk5 and ephexin1 which in turn modulates actin cytoskeletal dynamics.3

SUMMARY Animals generate movement by engaging spinal circuits that direct precise sequences of muscle contraction, but the identity and organizational logic of local interneurons that lie at the core of these circuits remain unresolved. Here we show that V1 interneurons, a major inhibitory population that controls motor output, fractionate into highly diverse subsets on the basis of the expression of nineteen transcription factors. Transcriptionally defined V1 subsets exhibit distinct physiological signatures and highly structured spatial distributions with mediolateral and dorsoventral positional biases. These positional distinctions constrain patterns of input from sensory and motor neurons, arguing that interneuron position is a determinant of microcircuit organization. Moreover, V1 diversity indicates that different inhibitory microcircuits exist for motor pools controlling hip, ankle, and foot muscles, revealing a variable circuit architecture for interneurons that control limb movement.