Alfredo Kirkwood
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Researcher at Department of Neuroscience, Johns Hopkins University
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Disinhibition is an obligatory initial step in the remodeling of cortical circuits by sensory experience, yet the underlying mechanisms remain unclear. Our investigation of mechanisms for disinhibition in the classical model of ocular dominance plasticity (ODP) uncovered an unexpected novel form of experience-dependent circuit plasticity. In layer 2/3 of mouse visual cortex monocular deprivation triggers an "all-or-none" elimination of approximately half the connections from local pyramidal cells onto parvalbumin-positive interneurons (Pyr[->]PV), without affecting the strength of the remaining connections. This loss of Pyr[->]PV connections is transient, lasting one day only, has a critical period commensurate with the ODP critical period, and is contingent on a reduction of neuropentraxin2 (NPTX2), which normally stabilizes Pyr[->]PV connections. Bidirectional manipulations of NPTX2 functionality that prevent/promote the elimination Pyr[->]PV connections also promote/prevent ODP. We surmise, therefore, that this rapid and reversible loss of local Pyr[->]PV circuitry gates experience-dependent cortical plasticity.
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Neurobiology of Aging, 2020-08-01
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Neurobiology of Aging
Altered neural excitability is considered a prominent contributing factor to cognitive decline during aging. A clear example is the excess neural activity observed in several temporal lobe structures of cognitively impaired older individuals in rodents and humans. At a cellular level, aging-related changes in mechanisms regulating intrinsic excitability have been well examined in pyramidal cells of the CA1 hippocampal subfield. Studies in the inbred Fisher 344 rat strain document an age-related increase in the slow afterhyperpolarization (AHP) that normally occurs after a burst of action potentials, and serves to reduce subsequent firing. We evaluated the status of the AHP in the outbred Long-Evans rat, a well-established model for studing individual differences in neurocognitive aging. In contrast to the findings reported in the Fisher 344 rats, in the Long-Evan rats we detected a selective reduction in AHP in cognitively impaired aged individuals. We discuss plausible scenarios to account for these differences and also discuss possible implications of these differences. ### Competing Interest Statement The authors have declared no competing interest.
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Cortical synapses exhibit a marked short-term depression (STD) during sustained activation, largely due to the depletion of synaptic resources (vesicles). In most excitatory synapses the rate of replenishment of depleted vesicles is constant, determining an inverse relationship between the STD level and the activation rate, which theoretically, severely limits rate coding capabilities in these synapses. In contrast STD in inhibitory synapses made by parvalbumin-positive interneurons (PV-INs) is less affected by usage. We examined STD of the PV-IN to Pyramidal cell synapse in the mouse visual cortex, and found that in these synapses the recovery of depleted resources is not constant but increases linearly with the frequency of use. By combining modeling, dynamic clamp and optogenetics, we demonstrated that this dynamic regulation of recovery enables PV-INs to reduce pyramidal cell firing in a linear manner, which, theoretically, is crucial for controlling the gain of cortical visual responses.
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Scientific Reports, 2019-02-08
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Scientific Reports
Ionic currents, whether measured as conductance amplitude or as ion channel transcript levels, can vary many-fold within a population of identified neurons. This variability has been observed in multiple invertebrate neuronal types, but they do so in a coordinated manner such that their magnitudes are correlated. These conductance correlations are thought to reflect a tight homeostasis of cellular excitability that enhances the robustness and stability of neuronal activity over long stretches of time. Notably, although such ionic current correlations are well documented in invertebrates, they have not been reported in vertebrates. Here we demonstrate with two examples, identified mouse hippocampal granule cells and cholinergic basal forebrain neurons, that ionic current correlations is a ubiquitous phenomenon expressed by a number of species across phyla.
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eLife, 2020-05-20
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eLife
Neuromodulatory systems are essential for remodeling glutamatergic connectivity during experience-dependent cortical plasticity. This permissive/enabling function of neuromodulators has been associated with their capacity to facilitate the induction of Hebbian forms of long-term potentiation (LTP) and depression (LTD) by affecting cellular and network excitability. In vitro studies indicate that neuromodulators can also affect the expression of Hebbian plasticity in a pull-push manner: receptors coupled to the G-protein Gs promote the expression of LTP at the expense of LTD, and Gq-coupled receptors promote LTD at the expense of LTD. Here we show that the pull-push mechanism can be recruited in vivo by pairing brief monocular stimulation with pharmacological or chemogenetical activation of Gs- or Gq-coupled receptors to respectively enhance or reduce visual cortical responses. These changes were stable, can be induced in adults after the termination of the critical period for juvenile ocular dominance plasticity, and can rescue deficits induced by prolonged monocular deprivation.