Spatial regulation of coordinated excitatory and inhibitory synaptic plasticity at dendritic synapses.

The induction of synaptic plasticity at an individual dendritic glutamatergic spine can affect neighboring spines. This local modulation generates dendritic plasticity microdomains believed to expand the neuronal computational capacity. Here, we investigate whether local modulation of plasticity can also occur between glutamatergic synapses and adjacent GABAergic synapses. We find that the induction of long-term potentiation at an individual glutamatergic spine causes the depression of nearby GABAergic inhibitory synapses (within 3 µm), whereas more distant ones are potentiated. Notably, L-type calcium channels and calpain are required for this plasticity spreading. Overall, our data support a model whereby input-specific glutamatergic postsynaptic potentiation induces a spatially regulated rearrangement of inhibitory synaptic strength in the surrounding area through short-range heterosynaptic interactions. Such local coordination of excitatory and inhibitory synaptic plasticity is expected to influence dendritic information processing and integration.

Kainate Receptor Activation Shapes Short-Term Synaptic Plasticity by Controlling Receptor Lateral Mobility at Glutamatergic Synapses.

Kainate receptors (KARs) mediate postsynaptic currents with a key impact on neuronal excitability. However, the molecular determinants controlling KAR postsynaptic localization and stabilization are poorly understood. Here, we exploit optogenetic and single-particle tracking approaches to study the role of KAR conformational states induced by glutamate binding on KAR lateral mobility at synapses. We report that following glutamate binding, KARs are readily and reversibly trapped at glutamatergic synapses through increased interaction with the ß-catenin/N-cadherin complex. We demonstrate that such activation-dependent synaptic immobilization of KARs is crucial for the modulation of short-term plasticity of glutamatergic synapses. Thus, the present study unveils the crosstalk between conformational states and lateral mobility of KARs, a mechanism regulating glutamatergic signaling, particularly in conditions of sustained synaptic activity.

Inter-Synaptic Lateral Diffusion of GABAA Receptors Shapes Inhibitory Synaptic Currents.

The 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.

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity.

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 ß-amyloid (Aß) disrupts actin and microtubule (MT) dynamics via activation of RhoA and inhibition of histone deacetylase 6 (HDAC6) in cultured hippocampal neurons. The contact of Aß 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 Aß 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.