A Quantitative Ultrastructural Study of the Effects of Phenylacetate on Synaptic Organization in the Developing Rat Cerebral Cortex

Abstract

Male rats were injected with either phenylacetate (PA; a phenylalanine metabolite) or saline (control). Osmicated tissue from the parietal cortex was analyzed qualitatively and quantitatively, attention being focused on possible synaptic changes in the molecular layer. PA-treated rats differed from controls in the following ways: a 20% decrease in body weight at 21 days, and a reduction in brain weight at 10 and 21 days; the presence of 'atypical' profiles (possibly derived from axonal growth cones) in the neuropil; a lag in the accretion of synapses per 100 μm² of tissue, and of vesicles per μm²of presynaptic terminal; the presence of a 'crossover' in the developmental trend for several synaptic organizational parameters between days 15 and 21; an elevation in synaptic density at day 21; an increased proportion of negatively curved synapses at 21 days; a significant difference in the preponderance of axodendritic synapses over days 7–21. This suggests that the metabolism of some neurons in the PA brain is initially different from normal, with a lag in synaptic development being evident. The increase in synaptic density and the relative preponderance of other synaptic parameters at 21 days signifies that an initial lag in development may alter the developmental scheme. This may be coupled with changes in synaptic efficacy and connectivity.

Glutamatergic Dysfunction and Synaptic Ultrastructural Alterations in Schizophrenia and Autism Spectrum Disorder: Evidence from Human and Rodent Studies

“…This theory was supported by the fact that the administration of barbiturates changed the curvature of synapses towards more curved shapes [190]. Later studies have shown that not only a variety of anesthetics [191] but also other parameters influence the curvature of synapses in healthy individuals, such as age [185,192] and nutrition [193], making it difficult to draw a conclusion about its relevance. The latest studies performed in rodent hippocampus suggested that changes in synaptic curvature may influence synaptic efficacy associated with long-term depression and LTP [194].…”

A Biochemical Explanation of Phenyl Acetate Neurotoxicity in Experimental Phenylketonuria

“…A simulation of PKU has been induced in the rat exposed to PA during the first 21 days of life (Loo et al, 1978;Wen et al, 1980). Evidence pointing to PA as the major cause of the brain dysfunction in PKU has been accumulating (Loo et al, 19800; Robain et a]., 1981Robain et a]., , 1983Baumann and Kemper, 1982;Oorschot and Jones, 1984). Information on the biochemical mechanism of the neurotoxic action of PA should therefore contribute to a better understanding of the disease and the development of preventive measures.…”