Person:

Yao, Wei-Dong

Spike timing-dependent plasticity (STDP) of glutamatergic synapses is a Hebbian associative plasticity that may underlie certain forms of learning. A cardinal feature of STDP is its dependence on the temporal order of presynaptic and postsynaptic spikes during induction: pre–post (positive) pairings induce t-LTP (timing-dependent long-term potentiation) whereas post–pre (negative) pairings induce t-LTD (timing-dependent long-term depression). Dopamine (DA), a reward signal for behavioral learning, is believed to exert powerful modulations on synapse strength and plasticity, but its influence on STDP has remained incompletely understood. We previously showed that DA extends the temporal window of t-LTP in the prefrontal cortex (PFC) from +10 to +30 ms, gating Hebbian t-LTP. Here, we examined DA modulation of synaptic plasticity induced at negative timings in layer V pyramidal neurons on mouse medial PFC slices. Using a negative timing STDP protocol (60 post–pre pairings at 0.1 Hz, δt = -30 ms), we found that DA applied during post–pre pairings did not produce LTD, but instead enabled robust LTP. This anti-Hebbian t-LTP depended on GluN2B-containing NMDA receptors. Blocking D1- (D1Rs), but not D2- (D2Rs) class DA receptors or disrupting cAMP/PKA signaling in pyramidal neurons also abolished this atypical t-LTP, indicating that it was mediated by postsynaptic D1R-cAMP/PKA signaling in excitatory synapses. Unlike DA-enabled Hebbian t-LTP that requires suppression of GABAergic inhibition and cooperative actions of both D1Rs and D2Rs in separate PFC excitatory and inhibitory circuits, DA-enabled anti-Hebbian t-LTP occurred under intact inhibitory transmission and only required D1R activation in excitatory circuit. Our results establish DA as a potent modulator of coincidence detection during associative synaptic plasticity and suggest a mechanism by which DA facilitates input-target association during reward learning and top-down information processing in PFC circuits.

Botulinum neurotoxins (BoNT/A-G) are well-known to act by blocking synaptic vesicle exocytosis. Whether BoNTs disrupt additional neuronal functions has not been addressed. Here we report that cleavage of syntaxin 1 (Syx 1) by BoNT/C and cleavage of SNAP-25 by BoNT/E both induce degeneration of cultured rodent and human neurons. Furthermore, although SNAP-25 cleaved by BoNT/A can still support neuron survival, it has reduced capacity to tolerate additional mutations and also fails to pair with syntaxin isoforms other than Syx 1. Syx 1 and SNAP-25 are well-known for mediating synaptic vesicle exocytosis, but we found that neuronal death is due to blockage of plasma membrane recycling processes that share Syx 1/SNAP-25 for exocytosis, independent of blockage of synaptic vesicle exocytosis. These findings reveal neuronal cytotoxicity for a subset of BoNTs and directly link Syx 1/SNAP-25 to neuron survival as the prevalent SNARE proteins mediating multiple fusion events on neuronal plasma membranes.

Many neurodegenerative diseases, such as frontotemporal dementia (FTD), are associated with behavioral deficits, but the anatomical and molecular bases remain poorly understood. Here we show that forebrain-specific expression of FTD-associated mutant CHMP2B causes several age-dependent neurodegenerative phenotypes, including social behavioral impairments. The social deficits were accompanied by a change in AMPA receptor (AMPAR) composition, leading to imbalance between Ca2+-permeable and -impermeable AMPARs. Expression of most AMPAR subunits was regulated by the brain-enriched microRNA (miR-124), whose abundance was markedly decreased in the superficial layers of cerebral cortex of FTD mice. We found similar changes in miR-124 and AMPAR levels in the frontal cortex and iPSC-derived neurons of subjects with behavioral variant FTD. Moreover, miR-124 expression in the medial prefrontal cortex decreased AMPAR levels and partially rescued behavioral deficits. Knockdown of Gria2 also alleviated social impairments in FTD mice. Our results identify a novel mechanism involving miR-124 and AMAPRs in regulating social behavior in FTD and suggest a potential therapeutic avenue.

Homeostatic synaptic plasticity is a compensatory response to alterations in neuronal activity. Chronic deprivation of neuronal activity results in an increase in synaptic AMPA receptors (AMPARs) and postsynaptic currents. The biogenesis of GluA2-lacking, calcium-permeable AMPARs (CP-AMPARs) plays a crucial role in the homeostatic response; however, the mechanisms leading to CP-AMPAR formation remain unclear. Here we show that the microRNA, miR124, is required for the generation of CP-AMPARs and homeostatic plasticity. miR124 suppresses GluA2 expression via targeting its 3′-UTR, leading to the formation of CP-AMPARs. Blockade of miR124 function abolishes the homeostatic response, whereas miR124 overexpression leads to earlier induction of homeostatic plasticity. miR124 transcription is controlled by an inhibitory transcription factor EVI1, acting by association with the deacetylase HDAC1. Our data support a cellular cascade in which inactivity relieves EVI1/HDAC-mediated inhibition of miR124 gene transcription, resulting in enhanced miR124 expression, formation of CP-AMPARs and subsequent induction of homeostatic synaptic plasticity.