Maintenance of neuronal polarity and regulation of cytoskeletal dynamics are vital during development and to uphold synaptic activity in neuronal networks. Here we show that soluble b-amyloid (Ab) disrupts actin and microtubule (MT) dynamics via activation of RhoA and inhibition of histone deacetylase 6 (HDAC6) in cultured hippocampal neurons. The contact of Ab with the extracellular membrane promotes RhoA activation, leading to growth cone collapse and neurite retraction, which might be responsible for hampered neuronal pathfinding and migration in Alzheimer's disease (AD). The inhibition of HDAC6 by Ab increases the level of heterodimeric acetylated tubulin and acetylated tau, both of which have been found altered in AD. We also find that the loss of HDAC6 activity perturbs the integrity of axon initial segment (AIS), resulting in mislocalization of ankyrin G and increased MT instability in the AIS concomitant with loss of polarized localization of tau and impairment of action potential firing.

SummaryThe lateral mobility of neurotransmitter receptors has been shown to tune synaptic signals. Here we report that GABAA receptors (GABAARs) can diffuse between adjacent dendritic GABAergic synapses in long-living desensitized states, thus laterally spreading “activation memories” between inhibitory synapses. Glutamatergic activity limits this inter-synaptic diffusion by trapping GABAARs at excitatory synapses. This novel form of activity-dependent hetero-synaptic interplay is likely to modulate dendritic synaptic signaling.

Highlights d LTP of individual dendritic spines causes iLTD at neighboring GABAergic synapses d Interaction between single-spine LTP and iLTD occurs in the spatial range of ±3 mm d This iLTD depends on the local dendritic calcium increase and calpain activation d iLTD is associated with reduced gephyrin clustering and increased GABAAR mobility

Highlights d Anchoring of KARs at glutamatergic synapses depends on receptor-glutamate binding d KARs activation/desensitization promotes receptors trapping at glutamatergic synapses d N-cadherins mediate the KAR activation/desensitizationdependent anchoring at synapses d Synaptic trapping of desensitized KARs affects short-term synaptic plasticity

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