SUMMARY Network activity homeostatically alters synaptic efficacy to constrain neuronal output. However, it is unclear how such compensatory adaptations coexist with synaptic information storage, especially in established networks. Here, we report that in mature hippocampal neurons in vitro, network activity preferentially regulated excitatory synapses within the proximal dendrites of CA3 neurons. These homeostatic synapses exhibited morphological, functional, and molecular signatures of the specialized contacts between mossy fibers of dentate granule cells and thorny excrescences (TEs) of CA3 pyramidal neurons. In vivo TEs were also selectively and bidirectionally altered by chronic activity changes. TE formation required presynaptic synaptoporin and was suppressed by the activity-inducible kinase, Plk2. These results implicate the mossy fiber-TE synapse as an independently tunable gain control locus that permits efficacious homeostatic adjustment of mossy fiber-CA3 synapses, while preserving synaptic weights that may encode information elsewhere within the mature hippocampal circuit.

Conjugated oligoelectrolytes (COEs) are a relatively new class of synthetic organic molecules with, as of yet, untapped potential for use in organic optoelectronic devices and bioelectronics systems. COEs also offer a novel molecular approach to biosensing, bioimaging, and disease therapy. Substantial progress has been made in the past decade at the intersection of chemistry, materials science and the biological sciences developing COEs and their polymer analogues, namely conjugated polyelectrolytes (CPEs), into synthetic systems with biological and biomedical utility. CPEs have traditionally attracted more attention in arenas of sensing, imaging, and therapy. However, the precisely-defined molecular structures and interactions of COEs offer potential key advantages over CPEs, including higher reliability and fluorescence quantum efficiency, larger diversity of subcellular targeting strategies, and improved selectivity to biomolecules. Here, the unique -and sometimes overlooked -properties of COEs are discussed and the noticeable progress in their use for biological sensing, imaging and therapy is reviewed.Received: ((will be filled in by the editorial staff))Revised: ((will be filled in by the editorial staff))

Homeostatic plasticity is a negative feedback mechanism that stabilizes neurons during periods of perturbed activity. The best-studied form of homeostatic plasticity in the central nervous system is the scaling of excitatory synapses. Postsynaptic AMPA-type glutamate receptors (AMPARs) can be inserted into synapses to compensate for neuronal inactivity or removed to compensate for hyperactivity. However, the molecular mechanisms underlying the homeostatic regulation of AMPARs remain elusive. Here, we show that the expression of GRIP1, a multi-PDZ (postsynaptic density 95/discs large/zona occludens) domain AMPAR-binding protein, is bidirectionally altered by neuronal activity. Furthermore, we observe a subcellular redistribution of GRIP1 and a change in the binding of GRIP1 to GluA2 during synaptic scaling. Using a combination of biochemical, genetic, and electrophysiological methods, we find that loss of GRIP1 blocks the accumulation of surface AMPARs and the scaling up of synaptic strength that occur in response to chronic activity blockade. Collectively, our data point to an essential role of GRIP1-mediated AMPAR trafficking during inactivity-induced synaptic scaling.synaptic scaling | postsynaptic density | glutamate receptor | PDZ domain

The search for memory is one of the oldest quests in written human history. For at least two millennia, we have tried to understand how we learn and remember. We have gradually converged on the brain and looked inside it to find the basis of knowledge, the trace of memory. The search for memory has been conducted on multiple levels, from the organ to the cell to the synapse, and has been distributed across disciplines with less chronological or intellectual overlap than one might hope. Frequently, the study of the mind and its memories has been severely restricted by technological or philosophical limitations. However, in the last few years, certain technologies have emerged, offering new routes of inquiry into the basis of memory. The 2016 Kavli Futures Symposium was devoted to the past and future of memory studies. At the workshop, participants evaluated the logic and data underlying the existing and emerging theories of memory. In this paper, written in the spirit of the workshop, we briefly review the history of the hunt for memory, summarizing some of the key debates at each level of spatial resolution. We then discuss the exciting new opportunities to unravel the mystery of memory.