A Novel Role for Phospholamban in the Thalamic Reticular Nucleus - PROJECT SUMMARY
The thalamic reticular nucleus (TRN) is a critical brain region that greatly influences vital neurobehavioral
processes, including attention and the generation of sleep rhythms. Most recently, TRN dysfunction was
suggested to underlie hyperactivity, attention deficits, and sleep disturbances observed across various
devastating neurodevelopmental disorders, including autism, schizophrenia and attention-deficit/hyperactivity
disorder (ADHD). Notably, a highly specialized sarco-endoplasmic reticulum calcium (Ca2+) ATPase 2
(SERCA2)-dependent Ca2+ signaling network operates in the dendrites of TRN neurons to generate and
regulate their high-frequency bursting activity. Phospholamban (PLN) is a crucial regulator of the SERCA2 with
an established role in maintaining Ca2+ homeostasis in the heart. Though the interaction of PLN with SERCA2
has been largely regarded as cardiac-specific, exciting preliminary data from our laboratory challenge this view
and suggest that the role of PLN extends beyond the cardiovascular system to impact the function of TRN
neurons. Specifically, solid preliminary evidence indicates that PLN protein is selectively expressed in the TRN
neurons of the adult mouse brain and that constitutive loss of PLN function in mice (PLNKO) results in
hyperactivity and cognitive deficits. Our overarching hypothesis is that PLN is a prominent Ca2+-handling
player in the TRN neurocircuitry involved in regulating the firing activity of TRN neurons and critical TRN-
dependent behaviors. To test this hypothesis, we will use constitutive and innovative conditional genetic
mouse models, in combination with sophisticated electrophysiological (i.e., whole-cell patch-clamping) and
behavioral approaches (i.e., the 5-choice serial-reaction time task; 5-CSRTT, and electroencephalography-
based polysomnography) to assess the role of PLN in regulating the burst-firing activity of TRN neurons, as
well as attention and sleep, two complex behaviors that map onto thalamic reticular circuits. The studies
outlined in the current NIH Small Research Grant (R03) proposal will functionally isolate the TRN as a brain
region where PLN regulates attention and sleep by affecting specific cellular processes. Performing this
research will enable future experiments aimed at more intensive dissection of the molecular and cellular
mechanisms implicated in the regulation of the PLN/SERCA2 pathway in TRN neurons, and will lay the
groundwork for considering PLN as a novel Ca2+-handling player in brain physiology and pathophysiology.
