Intrauterine Growth Restriction Affects Cerebellar Granule Cells in the Developing Guinea Pig Brain

Abstract

Intrauterine growth restriction (IUGR) can lead to adverse neurodevelopmental sequelae in postnatal life. However, the effects of IUGR on the cerebellum are still to be fully elucidated. A major determinant of growth and development of the cerebellum is proliferation and subsequent migration of cerebellar granule cells. Our objective was to determine whether IUGR, induced by chronic placental insufficiency (CPI) in guinea pigs, results in abnormal cerebellar development due to deficits suggestive of impaired granule cell proliferation and/or migration. CPI was induced by unilateral ligation of the uterine artery at mid-gestation, producing growth-restricted (GR) foetuses at 52 and 60 days of gestation (dg), and neonates at 1 week postnatal age (term approx. 67 dg). Controls were from sham-operated animals. In GR foetuses compared with controls at 52 dg, the external granular layer (EGL) width and internal granular layer (IGL) area were similar. In GR foetuses compared with controls at 60 dg: (a) the EGL width was greater (p < 0.005); (b) the IGL area was smaller (p < 0.005); (c) the density of Ki67-negative (postmitotic) granule cells in the EGL was greater (p < 0.01); (d) the somal area of Purkinje cells was reduced (p < 0.005), and (e) the linear density of Bergmann glia was similar. The EGL width in GR foetuses at 60 dg was comparable to that of 52 dg control and GR foetuses. The pattern of p27-immunoreactivity in the EGL was the inverse of Ki67-immunoreactivity at both foetal ages; there was no difference between control and GR foetuses at either age in the width of p27-immunoreactivity, or in the percentage of the EGL width that it occupied. In the molecular layer of GR neonates compared with controls there was an increase in the areal density of granule cells (p < 0.05) and in the percentage of migrating to total number of granule cells (p < 0.01) at 1 week but not at 60 dg (p > 0.05). Thus, we found no specific evidence that IUGR affects granule cell proliferation, but it alters the normal program of migration to the IGL and, in addition, the development of Purkinje cells. Such alterations will likely affect the development of appropriate circuitry and have implications for cerebellar function.

Intrauterine Growth Restriction and Hyperoxia as a Cause of White Matter Injury

“…Uteroplacental insufficiency is the most common cause of IUGR in developed countries [8]. Currently, the predominant methods used to induce IUGR in animal models are maternal caloric and protein restriction and bilateral uterine artery ligation [5], [9], [10]. A new murine model of IUGR has been developed which infuses an analog of thromboxane A 2 (TXA 2 ), a vasoconstrictor that is overly expressed in mothers whose pregnancies are complicated by hypertension, cigarette smoking, and poorly controlled diabetes.…”

Adverse neuropsychiatric development following perinatal brain injury: from a preclinical perspective

“…Neuropathological consequences include reductions in total brain volume, myelination deficits and impaired brain connectivity 39 . Furthermore, unilateral ligation of the uterine artery at mid-gestation was associated with ventriculomegaly, reduced basal ganglia volume, impaired synaptogenesis and altered cerebellar Purkinje cell development in the guinea-pig brain at adolescence, resembling anatomical changes found in some individuals with SZ 18,[51][52][53][54] . Of note, prepulse inhibition (PPI) of the acoustic startle response (ASR) was reduced 53 .…”

Prenatal treatment with metronidazole induces cerebellar folia alteration in guinea pig fetuses

“…The foliation itself and the final fixed number of 10 folia point to the genetic basis of this process in which the complexity and number of subsegments increases in evolutionarily higher mammalian species [24,40]. Several chemicals [2][3][4][5], radiation [6], the absence of nutritional factors [7,8] as well as genetic mutations [41,42] are linked to the disturbance in the cerebellar cortex and folia development. Changes such as hypofissure, malposition and agenesis of the folia usually dominate.…”

“…The first findings of neuronal migration based on neuronal-glial interaction were described in a cerebellar development model [1]. Due to its specific structure, the cerebellum has so far been the subject of numerous studies examining the neurotoxic potential of different chemicals [2][3][4][5], ionizing radiation [6], as well as deficiencies of specific nutritional factors [7,8].…”