Duchenne Muscular Dystrophy (DMD), a muscle degenerative disorder, also affects CNS function and can result in cognitive impairment. In brain full length dystrophin is localized to the post synaptic nerve ending of inhibitory GABA-ergic synapses. Novel alternatively spliced dystrophin isoforms have been identified, these differ from the already identified dystrophin through the substitution of exon 78 by a unique and longer 38 amino acid sequence, named delta exon. We have termed isoforms expressing these isoforms the delta dystrophins. The delta dystrophins have been shown to be expressed in the brain but not in skeletal muscle. Subcellular fractionation studies show that full length delta dystrophin shows a different pattern of subcellular localization to full length classical dystrophin, Dp427. Dp 427 is highly enriched in the post synaptic density fraction whereas full length delta dystrophin is most enriched in the microsomal fraction. The two isoforms also show a difference in regional expression levels. Dp427 is abundant in cerebellum and in forebrain PSDs whereas full length dystrophin is expressed relatively weakly in cerebellum compared to forebrain. These observations raised the possibility that delta exon 78 is associated with the alternative trafficking. However, transfection of cultures of dissociated hippocampal neuronal with EGFP-plasmids containing C-terminal fragments of either classical or delta dystrophins shows a similar pattern of localization. The detailed localisation of both classical and delta dystrophins in primary cortical neuronal cultures has been investigated by fluorescence immunocytochemistry using isoform specific antibodies. The results show that delta dystrophins are expressed in a larger number of neurons than the classical dystrophins. Delta dystrophins are localized primarily to the dendritic compartment. Strikingly we found no evidence for the presence of delta dystrophins in dendritic spines or at post synaptic nerve endings. Co-localization studies with GABAergic and glutamatergic markers shows that delta dystrophin is not exclusively associated with GABA-ergic neurons. The present data suggest that classical and delta dystrophins show strikingly different patterns of cellular and subcellular localization in brain and suggests that they are not present within the same dystrophin protein complexes in brain.