Impaired Hypercarbic and Hypoxic Responses from Developmental Loss of Cerebellar Purkinje Neurons: Implications for Sudden Infant Death Syndrome

Abstract

Impaired responsivity to hypercapnia or hypoxia is commonly considered a mechanism of failure in Sudden Infant Death Syndrome (SIDS). The search for deficient brain structures mediating flawed chemosensitivity typically focuses on medullary regions; however, a network that includes Purkinje cells of the cerebellar cortex and its associated cerebellar nuclei also helps mediate responses to CO2 and O2 challenges, and assists integration of cardiovascular and respiratory interactions. Although cerebellar nuclei contributions to chemoreceptor challenges in adult models are well described, Purkinje cell roles in developing models are unclear. We used a model of developmental cerebellar Purkinje cell loss to determine if such loss influenced compensatory ventilatory responses to hypercapnic and hypoxic challenges. Twenty-four Lurcher mutant mice and wildtype controls were sequentially exposed to 2% increases in CO2 (0%-8%), or 2% reductions in O2 (21%-13%) over four minutes, with return to room air (21% O2 / 79% N2 / 0% CO2) between each exposure. Whole-body plethysmography was used to continuously monitor tidal volume (TV) and breath frequency (f). Increased f to hypercapnia was significantly lower in Mutants, slower to initiate, and markedly lower in compensatory periods, except for very high (8%) CO2 levels. The magnitude of TV changes to increasing CO2 appeared smaller in Mutants, but only approached significance. Smaller, but significant differences emerged in response to hypoxia, with Mutants showing smaller TV when initially exposed to reduced O2, and lower f following exposure to 17% O2. Since cerebellar neuropathology appears in SIDS victims, developmental cerebellar neuropathology may contribute to SIDS vulnerability.

The Cerebellum and SIDS: Disordered Breathing in a Mouse Model of Developmental Cerebellar Purkinje Cell Loss during Recovery from Hypercarbia

“…Lc/ + mice and their WT littermates showed similar patterns of respiration when breathing room air at baseline. This finding further substantiates earlier results, indicating that cerebellar Purkinje cell loss has little effect on components of eupneic breathing ( 11 , 12 , 24 ).…”

“…Experimental data were collected during light hours using a WBP system (Emka Technologies, Falls Church, VA, USA), as previously described ( 24 ). Briefly, a transducer was mounted to the WBP device, which converted pressure differentials in the chamber caused by respiration into electrical signals that were then transmitted to, and interpreted by, the software.…”

“…However, such lesions have little effect on relaxed, rhythmic breathing ( 10 , 23 ). Additionally, Lurcher mutant mice ( Lc/ +) with global, developmental cerebellar Purkinje cell loss show reduced respiratory responses following exposure to increased environmental CO 2 ( 24 ), an outcome interpreted as a reduction in sensitivity to increased blood CO 2 levels ( 25 – 27 ).…”

“…To determine if loss of cerebellar Purkinje cells results in distressed breathing following exposure to increased environmental CO 2 , we used whole body plethysmography (WBP) to investigate the hypothesis that Lurcher mutants heterozygous for the Lurcher spontaneous mutation ( Grid2 Lc ), would exhibit disordered breathing patterns during recovery from hypercapnia, in comparison to wild-type (WT) controls. Lurcher mice were selected because we had previously observed that deficits in breath frequency appeared during recovery, following exposure to low levels of CO 2 ( 24 ). In the current study, we specifically targeted two components of breath frequency, including TV and EEP periods.…”

cAMP-PKA-CaMKII signaling pathway is involved in aggravated cardiotoxicity during Fuzi and Beimu Combination Treatment of Experimental Pulmonary Hypertension

“…The rats undergoing non-invasive pulmonary function were monitored by whole-body barometric plethysmography (WBP; EMKA Technologies, Paris, France) 46 . Rats were placed in a plethysmograph chamber, and a 10-min accommodation was allowed before analysis.…”