Breakdown of oligodendrocyte-neuron interactions in white matter (WM), such as the loss of myelin, results in axonal dysfunction and hence a disruption of information processing between brain regions. The major feature of leukodystrophies is the lack of proper myelin formation during early development or the onset of myelin loss late in life. These early childhood WM diseases are described as hypomyelination or dysmyelination arising from a primary block in normal myelin synthesis because of a genetic mutation expressed in oligodendrocytes, or failure in myelination secondary to neuronal or astroglial dysfunctions (van der Knaap 2001 Dev. Med. Child Neurol. 43:705-712). Here, we describe the pathophysiological parameters of Canavan disease (CD), caused by genetic mutations of the aspartoacylase (ASPA) gene, a metabolic enzyme restricted in the central nervous system (CNS) to oligodendrocytes. CD presents pathophysiological dysfunctions similar to diseases caused by myelin gene mutations, such as Pelizaeus-Merzbacher disease (PMD) and several animal models, such as myelin deficient rat (md), jimpy (jp), shiverer (sh), and quaking (qk viable) mutant mice. These single gene mutations have pleiotropic effects, whereby the alteration of one myelin gene expression disrupts functional expression of other oligodendrocyte genes with an outcome of hypomyelination/dysmyelination. Among all of the known leukodystrophies, CD is the first disorder, which was approved and tested for the adeno-associated virus vector (AAV)-ASPA gene therapy (Leone et al. 2000 Ann. Neurol. 48:27-38; Janson et al. 2001 Trends Neurosci. 24:706-712) without much success following the first two attempts. ASPA gene delivery attempts in animal models have shown a lowering of N-acetyl L-aspartate and a change in motor functions, while sponginess of the WM, a characteristic of CD remained unchanged (Matalon et al. 2003 Mol. Ther. 7 (5, Part 1):580-587; McPhee et al. 2005 Brain Res. Mol. Brain Res. 135:112-121) even with better viral serotype and delivery of the gene during early phase of development (Klugmann et al. 2005 Mol. Ther. 11:745-753). While different approaches are being sought for the success of gene therapy, there are pivotal developmental questions to address regarding the specific regions of the CNS and cell lineages that become the target for the onset and progression of CD symptoms from early to late stages of development.

Studies in humans and animal models link maternal infection and imbalanced levels of inflammatory mediators in the foetal brain to the aetiology of neuropsychiatric disorders. In a number of animal models, it was shown that exposure to viral or bacterial agents during a period that corresponds to the second trimester in human gestation triggers brain and behavioural abnormalities in the offspring. However, little is known about the early cellular and molecular events elicited by inflammation in the foetal brain shortly after maternal infection has occurred. In this study, maternal infection was mimicked by two consecutive intraperitoneal injections of 200 μg of LPS (lipopolysaccharide)/kg to timed-pregnant rats at GD15 (gestational day 15) and GD16. Increased thickness of the CP (cortical plate) and hippocampus together with abnormal distribution of immature neuronal markers and decreased expression of markers for neural progenitors were observed in the LPS-exposed foetal forebrains at GD18. Such effects were accompanied by decreased levels of reelin and the radial glial marker GLAST (glial glutamate transporter), and elevated levels of pro-inflammatory cytokines in maternal serum and foetal forebrains. Foetal inflammation elicited by maternal injections of LPS has discrete detrimental effects on brain development. The early biochemical and morphological changes described in this work begin to explain the sequelae of early events that underlie the neurobehavioural deficits reported in humans and animals exposed to prenatal insults.

Canavan disease (CD) is a neurodegenerative disease, caused by a deficiency in the enzyme aspartoacylase (ASPA). This enzyme has been localized to oligodendrocytes; however, it is still undefined how ASPA deficiency affects oligodendrocyte development. In normal mice the pattern of ASPA expression coincides with oligodendrocyte maturation. Therefore, postnatal oligodendrocyte maturation was analyzed in ASPA-deficient mice (CD mice). Early in development, CD mice brains showed decreased expression of neural cell markers that was later compensated. In addition, the levels of myelin proteins were decreased along with abnormal myelination in CD mice compared to wild-type (WT). These defects were associated with increased global levels of acetylated histone H3, decreased chromatin compaction and increased GFAP protein, a marker for astrogliosis. Together, these findings strongly suggest that, early in postnatal development, ASPA deficiency affects oligodendrocyte maturation and myelination.