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Paradis, S.

Publications and source records attributed to Paradis, S..

3 recordsLinked to original sources

Stable memory and computation in randomly rewiring neural networks

Our brains must maintain a representation of the world over a period of time much longer than the typical lifetime of the biological components producing that representation. For example, recent research suggests that dendritic spines in the adult mouse hippocampus are transient with an average lifetime of approximately 10 days. If this is true, and if turnover is equally likely for all spines, approximately 95-percent of excitatory synapses onto a particular neuron will turn over within 30 days; however, a neurons receptive field can be relatively stable over this period. Here, we use computational modeling to ask how memories can persist in neural circuits such as the hippocampus and visual cortex in the face of synapse turnover. We demonstrate that Hebbian learning during replay of pre-synaptic activity patterns can integrate newly formed synapses into pre-existing memories. Further, we find that Hebbian learning during replay is sufficient to stabilize the receptive fields of hippocampal place cells in a model of the grid-cell-to-place-cell transformation in CA1 and of orientation-selective cells in a model of the center-surround-to-simple-cell transformation in V1. We also ask how synapse turnover affects memory in Hopfield networks with CA3-like, auto-associative properties. We find that attractors of Hopfield networks are remarkably stable if learning occurs during network reactivations. Together, these data suggest that a simple learning rule, correlative Hebbian plasticity of synaptic strengths, is sufficient to preserve neural representations in the face of synapse turnover, even in the absence of Hebbian structural plasticity.

neuroscience

Rem2 regulates distinct homeostatic mechanisms in visual circuit plasticity

Activity-regulated genes sculpt neural circuits in response to sensory experience. These calcium-sensitive genes generally fall into two categories: transcription factors and proteins that function at synapses. Yet little is known about activity-regulated, cytosolic proteins that transduce signals between the neuronal membrane and the nucleus. Using the visual system as a model, we investigated the role of the activity-regulated, non-canonical Ras-like GTPase Rem2 in vivo. We demonstrate that Rem2-/- mice fail to exhibit normal ocular dominance plasticity during the critical period. At the circuit level, cortical layer 2/3 neurons in Rem2-/- mice show deficits in both postsynaptic scaling up of excitatory synapses and misregulation of intrinsic excitability. Further, we reveal that Rem2 plays a novel, cell-autonomous role in regulating neuronal intrinsic excitability. Thus, Rem2 is a critical regulator of neural circuit function and distinct homeostatic plasticity mechanisms in vivo.\n\nHIGHLIGHTSO_LIRem2 is required in excitatory cortical neurons for normal ocular dominance plasticity\nC_LIO_LIRem2 regulates postsynaptic homoeostatic synaptic scaling up\nC_LIO_LIRem2 alters the intrinsic excitability of neurons in a cell-autonomous manner\nC_LI

neuroscience

The Ras-like GTPase Rem2 is a potent endogenous inhibitor of calcium/calmodulin-dependent kinase II activity

CaMKII is a well-characterized, abundant protein kinase that regulates a diverse set of functions in a tissue specific manner. For example, in heart muscle, CaMKII regulates Ca2+ homeostasis while in neurons CaMKII regulates activity-dependent dendritic remodeling and Long Term Potentiation (LTP), a biological correlate of learning and memory. Previously, we identified the noncanonical GTPase Rem2 as a critical regulator of dendrite branching and synapse formation in the vertebrate nervous system. Here, we report that Rem2 directly interacts with CaMKII and potently inhibits the activity of the intact holoenzyme, a previously undescribed function for the Rem2 protein. To date, only one other endogenous inhibitor of CaMKII has been described: CaMKIIN, which blocks CaMKII activity through binding to the catalytic domain. Our data suggest that Rem2 inhibits CaMKII through a novel mechanism, as inhibition requires the presence of the association domain of CaMKII. Our biochemical finding that Rem2 is a direct, endogenous inhibitor of CaMKII activity, coupled with known functions of Rem2 in neurons, provides a framework which will enable future experiments probing the physiological role of CaMKII inhibition in a cellular context.

biochemistry