CORTEX INHIBITION · Self-Inhibition of Interneurons in the Cerebral Cortex

Final Activity Report Summary - CORTEX INHIBITION (Self-inhibition of interneurons in the cerebral cortex)

In the mammalian brain, the cerebral cortex (neocortex) is the final destination of all sensory information, and the site where this information is integrated, stored and used to generate complex behaviours and cognitive functions. The activity of the neocortex is strictly controlled - if not entirely dictated - by locally projecting inhibitory GABAergic interneurons. Inhibitory interneurons are extremely heterogeneous and can be classified by anatomical and electrophysiological properties as well as by expression of specific Ca-binding proteins and neuropeptides. Diverse interneuron subtypes exert their specific function by contacting principal cortical cells - the pyramidal neurons - onto specific locations. For example, fast-spiking (FS) basket cells form inhibitory synapses on cell bodies, whereas another interneuron subtype (the low-threshold spiking cell, LTS) form GABAergic contacts with dendrites of pyramidal neurons. The former interneuron type will modulate the output of pyramidal cells (such as the synchronicity of their firing), while the latter will modulate excitatory inputs onto pyramidal neurons and it will thus apply a filter on dendrites, which route excitatory information coming from other cortical neurons to the cell body. We have previously shown that basket cells make functional inhibitory synaptic contacts with themselves (autapses) and that autaptic innervation modulates the precision of firing of these neurons. On the other hand, LTS interneurons do not make autaptic contacts but they respond to their own activity with a persistent inhibition of their excitability. This slow-self inhibition is accomplished by self-administration of endogenous cannabinoids by LTS cells. The original proposal aimed at getting better detailed information on the mechanisms and functions of these two forms of self-inhibitions in these two cortical neuron types. One important scientific achievement during the funding period of this grant was the finding that autaptic transmission in FS basket cells can operate in dual mode. Indeed, in addition to the known single transmission triggered by single spikes, FS cells can generate a delayed and prolonged self-inhibition in response to high-frequency trains of spikes. We have characterised this phenomenon and found that i) it is triggered by asynchronous release of synaptic vesicles at autaptic contacts; ii) it is dependent on presynaptic (pre-autaptic) Ca elevations with different sensitivity than single-spike mediated synchronous release; iii) it is modulated by the endogenous Ca-binding protein parvalbumin; iv) it changes the computational properties of postsynaptic neurons, with potential crucial consequences in keeping synchronised the firing between large populations of cortical neurons. This phenomenon will have important implications in disease states such as epilepsy, which is associated with high-frequency firing of cortical neurons, and schizophrenia, which is believed to be associated to the impaired functioning of specific inhibitory networks resulting from a reduced expression of parvalbumin. A second scientific achievement during the funding period was the identification of the molecule responsible for the slow self-inhibition in cortical LTS interneurons. Using a combination of electrophysiological and pharmacological approaches we identified the endogenous cannabinoid 2-arachidonoylglycerol as the actual molecule involved in this phenomenon. A third important achievement is represented by the discovery that also a significant percentage of excitatory pyramidal neurons of the neocortex self-administer endocannabinoids in a similar fashion shown by inhibitory LTS interneurons. This unexpected and interesting finding shifted the focus of our experiments. We found that i) pyramidal neurons self-inhibition occurs through activation of a specific potassium channel triggered by self-administration of endogenous cannabinoids; ii) this endocannabinoid-mediated self-modulation identifies a neocortical pyramidal neuron subtype with specific morphological characteristics.

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