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PV ≠ nRT: The role of the Distinct Thalamic Reticular Cell Types in Modulating Normal and Pathological Cortical Rhythms

Abstract

The thalamus is usually regarded as the gateway sensory information must cross to reach the cortex, the higher cognitive processing plant of the brain. This gateway is guarded by the nucleus Reticularis Thalami (nRT). The nRT is a group of inhibitory neurons that through synaptic connections to the thalamic relay nuclei, temper and control the information stream from thalamus to cortex. The nRT is known to play important roles in sickness and in health. In Chapter 2, we deconstruct the nRT to its various cell types and study their role in health. Traditionally, the nRT was described as a relatively homogenous structure: containing mostly Parvalbumin (PV) expressing neurons that have Transient-type (T-type) Calcium currents that confer onto them a burst firing mode. Recent work has suggested that not all nRT neurons are created equal. There have been studies suggesting that nRT cells have different molecular, electrophysiological, and circuit properties. In other areas of the brain, many of these differences between inhibitory neurons can be correlated with expression of markers such as PV and Somatostatin (SOM). We found this to hold true in the nRT as well. PV-expressing neurons are the bursting cells that are preferentially connected to somatosensory circuits and primed to be involved in generating the physiological sleep-spindle and pathological seizure activities. SOM-expressing neurons are non-bursting cells preferentially connected to limbic circuits, and seem to be less involved in sleep-spindles and seizures. In Chapter 3, we explore the role of the nRT neurons in an animal model of a human chronic neuropsychiatric disorder. Dravet syndrome (DS) is an incurable form of childhood epilepsy associated with severe seizures, autism, sleep disorders, and sudden death. DS is brought about by a loss-of-function mutation in the sodium channel gene SCN1A. SCN1A is highly expressed in nRT neurons. We found that the bursting nRT neurons had prolonged post-hyperpolarization rebound bursting activity, caused by a decrease in the small conductance calcium-activated potassium (SK) current. This increased bursting in nRT neurons caused intra-thalamic circuit hyperexcitability, which may cause the epileptic events observed in these mice. Increasing SK current through the SK agonist EBIO allowed us to normalize the bursting activity in nRT cells, reduce the intra-thalamic circuit hyperexcitability, and consequentially, reduce the seizure activity. Understanding the guardians of the gateway in sickness and in health ultimately help us understand how the brain transfers and processes information.

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