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

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 CO(2) and O(2) 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 CO(2) (0%-8%), or 2% reductions in O(2) (21%-13%) over four minutes, with return to room air (21% O(2) / 79% N2 / 0% CO(2)) 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%) CO(2) levels. The magnitude of TV changes to increasing CO(2) 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 O(2), and lower f following exposure to 17% O(2). Since cerebellar neuropathology appears in SIDS victims, developmental cerebellar neuropathology may contribute to SIDS vulnerability