Thalamic circuit modulation by astrocytes

The thalamus, a subcortical brain structure involved in key aspects of sensation, perception, cognition, and consciousness, is endowed with intrinsic rhythmogenic properties and extensive reciprocal connections with the cerebral cortex. These reciprocal connections form thalamo-cortico-thalamic circuits which generate, synchronize, and propagate physiological brain rhythms such as sleep spindles. Disruptions in these circuits can cause sleep deficits, and generation of pathological rhythms like seizures. While the canonical thalamo-cortico-thalamic circuit diagram consists entirely of neurons and their synaptic connections, mounting evidence points to the profound impact of astrocytes in dynamically modulating circuit components. Astrocytes are non-neuronal glial cells that play diverse, complex roles in mediating normal neuronal function in the developing and mature brain, at the synaptic and circuit levels, in both health and disease (Chapter 1). Astrocytes are well-positioned to govern crucial aspects of thalamic circuit function, such as excitability and rhythmogenesis, which can be disrupted in neurological disorders such as epilepsy (Chapter 2), but the precise mechanisms by which astrocytes modulate thalamic synapse and circuit function in development and disease are poorly understood. In Chapter 3, we demonstrate the critical role astrocytes play in shaping the developing thalamus of rodents by providing a key immune signal—IL-33 (interleukin-1 family cytokine interleukin-33)—to control the number of excitatory synapses. Its absence can lead to runaway excitation in the thalamus, paving the path for epileptic activity in mice. In Chapter 4, we demonstrate that reactive astrocytes can trigger aberrant synaptic and circuit function in the thalamus, providing strong evidence that they can be drivers, rather than mere bystanders, of injury-related pathological sequelae such as post-traumatic epilepsy and sleep disruption. Furthermore, we identify an aspect of reactive astrocytes—GABA transporter GAT-3 loss of function—sufficient to confer pathological excitability in an otherwise normal thalamic circuit, and one which may underlie thalamic dysfunction observed in cases of brain injuries. In Chapter 5, we discuss our findings which highlight distinct forms of thalamic synapse modulation by astrocytes, as well as common pathways of astrocytic function in brain development and degeneration; we also speculate on the potential role of astrocytes in mediating the distinctive computational properties of the reticular thalamic nucleus. Altogether, our findings add to the growing evidence supporting the critical role of astrocytes in the modulation of thalamic circuits in physiological and pathological settings