The functional significance of the sodium-potassium pump in motor control and movement disorders
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The sodium-potassium pump (NKA) is a ubiquitously expressed membrane protein. Mammalian neurons express two isoforms of the NKA’s catalytic α-subunit, the ubiquitous α1, and the neuron-specific α3. Mutations in the α3-NKA encoding protein ATP1A3 result in a spectrum of neurological disorders with pronounced motor deficits, including Rapid-Onset Dystonia Parkinsonism (RDP). The NKA has also been shown to facilitate activity-dependent changes in spinal motor networks via an ultra-slow afterhyperpolarisation (usAHP) which is thought to be an α3-NKA mediated current. First, we provide a comprehensive characterisation of a novel mouse model of RDP harbouring the T613M mutation of ATP1A3 most commonly found in patients. We show that T613M animals are hyperactive and hyperambulatory. We show involvement of spinal motor circuit pathology in this behaviour via a complete lack of usAHPs in T613M-affected motor neurons, and a reduced capacity for isolated spinal cords to regulate rhythmic motor output in response to large increases of intracellular sodium. We show that this deficiency is likely caused by a reduced capacity for T613M-affected α3-NKA to extrude sodium and therefore maintain sodium homeostasis. Next, we characterised post-discharge activity more generally in motor neurons from wildtype mice. We show that usAHPs are more commonly observed in the second postnatal week which may be due to an upregulation of α3-NKA protein expression in motor neurons alongside the development of weight-bearing locomotion. While the heterogenous distribution of usAHPs amongst populations of neurons was previously thought to be due to mosaicism of α3-NKA expression, we show that all lumbar motor neurons express α3-NKA. We present an alternative to this hypothesis, showing that usAHPs can be masked by competing conductances. Finally, we show that the post-discharge activity of a neuron can be modulated by extrinsic and intrinsic modulators to enhance or unmask certain post-discharge activity subtypes.
Thesis, PhD Doctor of Philosophy
Embargo Date: 2024-10-20
Embargo Reason: Thesis restricted in accordance with University regulations. Restricted until 20th October 2024
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