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Scientific Understanding of Consciousness |
Interneuron Activity-Dependent Transcriptional Switch
Science 11 September 2015: Vol. 349 no. 6253 pp. 1216-1220 Tuning of fast-spiking interneuron properties by an activity-dependent transcriptional switch Nathalie Dehorter, Gabriele Ciceri, Giorgia Bartolini, Lynette Lim, Isabel del Pino, Oscar Marín MRC Centre for Developmental Neurobiology, Medical Research Council, New Hunt's House, Guy's Campus, King’s College London, London SE1 1UL, UK. Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas and Universidad Miguel Hernández, 03550 Sant Joan d’Alacant, Spain. [paraphrase] The function of neural circuits depends on the generation of specific classes of neurons. Neural identity is typically established near the time when neurons exit the cell cycle to become postmitotic cells, and it is generally accepted that, once the identity of a neuron has been established, its fate is maintained throughout life. Here, we show that network activity dynamically modulates the properties of fast-spiking (FS) interneurons through the postmitotic expression of the transcriptional regulator Er81. In the adult cortex, Er81 protein levels define a spectrum of FS basket cells with different properties, whose relative proportions are, however, continuously adjusted in response to neuronal activity. Our findings therefore suggest that interneuron properties are malleable in the adult cortex, at least to a certain extent. Fast-spiking (FS), parvalbumin-expressing (PV+) basket cells make up the most abundant population of GABAergic interneurons in the cerebral cortex. Although they probably represent no more than 5% of the total neuronal population, they contribute to feedback and feedforward inhibition and are critically involved in the generation of network oscillations that are crucial for sensory perception, cognition, and behavior. In addition, FS PV+ basket cells play a prominent role in the regulation of plasticity and learning. Although it is likely that different classes of FS PV+ interneurons exist, the molecular mechanisms regulating their properties remain largely unknown. Our findings provide a mechanistic explanation for the activity-dependent regulation of interneuron properties through the transcriptional control of neuronal excitability and the modulation of synaptic inputs. Er81 has been previously shown to regulate the terminal differentiation of dopaminergic neurons and cerebellar granule cells. In the cortex, Er81 shapes information processing by modulating the intrinsic properties of FS interneurons through the regulation of the Kv1.1 channel subunit, the expression of which is necessary for delayed firing. Other factors are likely involved in this process, because loss of Er81 does not completely transform fast-spiking interneurons into nondelayed cells. Kv1.1 function is also regulated by ErbB4, a tyrosine kinase receptor that is highly expressed in the postsynaptic density of glutamatergic synapses contacting FS basket cells. This delineates a possible pathway through which synaptic activity may control Er81 expression to modulate the intrinsic properties of FS basket cells. Our results also support the notion that activity-dependent mechanisms play a prominent role in the specification of neuronal properties. However, in contrast to the classical view in which the “specification” typically refers to the process by which cells achieve and maintain a stable fate independent of environment, our results suggest that layer II-III fast spiking basket cells may not exist as distinct classes of interneurons, but rather as a continuum of interneurons with “tunable” characteristics that adapt to the changing environment. The observation that cortical circuits reversibly adapt to changing levels of activity by tuning the efficacy of delayed firing within the population of FS basket cells suggests a novel mechanism of network plasticity, and reinforces the notion that interneuron function is ultimately context dependent. Recent work has linked different configurations of FS basket cells, as revealed by distinct levels of PV expression, with learning and memory. Our analysis of Er81 conditional mutant mice indicate that drastic imbalances in network configuration are accompanied by population-driven changes in structural synaptic plasticity, through which FS basket cells may lose their ability to filter out relatively weak, asynchronous stimulus. [end of paraphrase]
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