Synapsin I/II double knockout mice and spontaneously hypertensive rats : two animal models with implications for neurological disorders

Abstract

SUMMARY

The synapsins are abundant phosphoproteins associated with synaptic vesicles. Although synapsins were among the first vesicle proteins discovered, their functions still remain incompletely understood. Previous studies have reported major decreases in the number of synaptic vesicles in synapsin deficient brains, but knowledge about which classes of vesicles are affected has been lacking. In the first part of this study, the consequences of the deletion of synapsin I and II for different subgroups of vesicles were studied in different brain regions.

It was recently reported by our group that the levels of VGLUT1, VGLUT2 and VGAT are decreased by approximately 40% in mice devoid of synapsin I and II. In this study, the main focus was on the effects on cholinergic vesicles, using VAChT as a cholinergic marker, in mice lacking synapsin I and II. The levels of different vesicular transporters were studied in three brain areas, the neostriatum, cortex and pons medulla. The levels of VGLUT-1, VGLUT-2 and VGAT were decreased by 30-50% in all the brain areas examined. In contrast, the levels of VAChT were decreased by only 23% in the neostriatum, and were present at the same levels as wild-type in cortex and pons medulla. We do not know whether the cholinergic terminals in striatum, cortex and pons medulla, differ regarding their dependence and co/localization with synapsins. Synaptic vesicles are covered with synapsins and could serve some role of vesicle stabilization. A decrease in synaptic vesicles in mice lacking synapsins could indicate that synapsins serve a role in vesicle stabilization. Lack of synapsins could therefore induce the vesicles to undergo spontaneous degradation..

In the second part of the study, the aim was to measure the amounts of proteins involved in the dopaminergic system in an animal model for the “attention deficity hyperactivity disorder” (ADHD). The spontaneous hypertensive rat (SHR) is the only animal model that has been found to demonstrate all the behavioural characteristics of ADHD, namely hyperactivity, impulsivity and problems with sustained attention. Since abnormal dopaminergic responses appear as one of main markers for ADHD, the amount of dopamine D1–like receptors was measured. Our results show an increase by 21% in the density of D1-like receptors in cerebrum. This increase in the amounts of D1-like receptors could be a compensatory mechanism for dopamine hypofunction (evt reduced dopamine release) in SHR, and confirms the hypothesis of a dysregulation of the dopaminergic system in ADHD. No difference was found in the levels of the D1-interacting protein, calcyon, or the enzyme which catalyzes the degradation of dopamine, COMT. Since many dopaminergic effects are mediated through interaction with glutamatergic neurotransmission, the levels of the NMDA-subunits of the NMDA-receptor were examined in neostriatum and cerebrum. No changes were detected on the protein level of NMDA-1 and NMDA-2A/B, but one cannot exclude their involvement in the aetiology of ADHD.