Chronic Hyponatremia Disrupts Gait Coordination in Rats that Persists Following Correction of Hyponatremia
Authors: Neckel Nathan D. , Xu Qin , Pillai Sambhu M. , Barsony Julia , Verbalis Joseph G. 
Published: April 2020

Multiple epidemiologic studies have associated chronic hyponatremia with bone fractures. Potential etiologies of the increased fracture rate are both metabolic (bone resorption leading to increased bone fragility) and neural (increased falls). Studies in humans and rats have found that hyponatremia causes alterations in gait, implicating gait instability as a potential cause of the increased fall rate in humans. Previous studies in rats indicated that the alterations in gait were reversible following correction of hyponatremia, but in these studies the hyponatremia was maintained for relatively short periods (3–4 weeks). Whether alterations in gait produced by more chronic hyponatremia can also be reversed by correction of hyponatremia has not been studied. The present studies directly address this question. 22‐month‐old F344BN F1‐hybrid rats were made hyponatremic using desmopressin continuous infusion while fed a liquid diet. After 4, 8 or 12 weeks (wks) of chronic hyponatremia, a cohort of the hyponatremic rats after each time point were corrected to a normal [Na+] by removal of the desmopressin minipumps and allowed to recover for 8 wks. Gait was assessed using the CatWalk apparatus (Noldus Inc, NE) at baseline (NN, [Na+]=142±6.2 mmol/L, n =67), after sustained hyponatremia (HN, 4 wks: [Na+]=111±4.7 mmol/L, n=16; 8 wks: [Na+]=107±4.0 mmol/L, n =13; 12 wks: [Na+]=114±4.7 mmol/L, n =18), 8 weeks after correction of the hyponatremia (HC, [Na+]=140±3.0 mmol/L, n =7, 7, 9), and in a group of equivalently aged normonatremic control rats (12 wks, n=9). Locomotor performance of all rats was compared to baseline performance. The results confirmed that chronic hyponatremia caused a significant disruption in gait coordination, as assessed by measurement of the delay (msec) between left forelimb and right hindlimb initial contact: NN=−13.66±0.42 msec; 4‐wk HN=−17.20±0.90 (p=0.02); 8‐wk HN=−21.21±1.31 (p<0.001); 12‐wk HN=−19.50±1.18 (p<0.001), while 12‐wk normonatremic control rats were no different from baseline: −12.17±2.19 (p=0.35). Correction of hyponatremia returned the abnormalities in gait coordination to baseline levels after 4 wks of hyponatremia, but not after 8 and 12 wks of sustained hyponatremia: 4‐wk HC=−11.78±1.58 (p=0.21); 8‐wk HC=−19.45±1.32 (p=0.02); 12‐wk HC=−21.12±1.80 (p<0.001). These results confirm previous results that gait is altered by chronic hyponatremia in rats, and that these defects are reversible after short periods of hyponatremia. However, longer periods of sustained hyponatremia caused greater disruptions of gait coordination, which did not return to baseline normonatremic levels following correction of hyponatremia. Our findings therefore suggest the possibility that chronic hyponatremia causes neuropathological changes in the brain that may lead to permanent alterations in limb coordination and subsequent gait instability, thereby increasing susceptibility to falls with resulting bone fractures.

Support or Funding Information

Supported by NIH grant R01‐AG053506.