In the neocortex, GABAergic interneurons make up ~25% of the entire neuronal population, but their activity is crucial, as they provide feed-forward and feedback inhibition and prevent development of epilepsy. Besides serving as mere controllers of excitation, inhibitory interneurons generate, pace and modulate the rhythmic activity of large neuronal populations, which is thought to be associated with several behavioural functions, as well as epileptiform activity.
Cortical interneurons represent a highly heterogeneous cell population, yet a few major subtypes can be identified, forming specific GABAergic networks and connectivity patterns. Our recent experiments revealed that fast spiking (FS) and low-threshold spiking (LTS) interneurons are controlled by distinct self-inhibitory mechanisms, each unique and powerful. FS cells form functional GABAergic autaptic contacts, which, once activated by their own firing, generate a fast, precise and transient inhibition.
In contrast, LTS cells, in response to their own repetitive discharges, generate a hyperpolarizing slow self inhibition (SSI) that is large, long-lasting and results from autocrine release of endocannabinoids. In this proposal we will address two major questions:
- In FS cells, how do autapses determine the overall inhibitory input onto these cells, coordinating inhibitory plasticity and network synchrony?
- What are the mechanisms and function of the endocannabinoid-dependent SSI in LTS cells?
Our approach will include single and paired whole cell recordings of rat interneurons in brain slices together with pharmacology, neuroanatomy and molecular biology.
The results of these experiments will address the central theme, i.e. mechanisms and function of self-inhibition in neocortical neurons and will lea d to a clearer understanding of how two major subclasses of interneurons regulate cortical excitability with relevant implications to normal cognitive functions, epilepsy, schizophrenia, and drug of abuse.
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