Role of Bassoon-mediated active zone integrity at different types of brain synapses for brain activity and cortex-dependent memory formation

Abstract

BackgroundThe properly controlled release of neurotransmitter at presynaptic active zones is crucial for brain function and performance. Bassoon is a major scaffolding protein involved in the organization of neurotransmitter release sites at excitatory, inhibitory and modulatory brain synapses. Global deficiency of functional Bassoon causes severe neurological conditions including disturbed patterns of brain activity and early-onset epilepsy. To distinguish the contribution of different types of synapses to this phenotype we generated conditional knockout (cKO) mice lacking the Bsn gene in (i) GABAergic interneurons expressing Cre recombinase under the control of the Dlx5/6 regulatory elements (BsnDlx5/6 cKO), (ii) glutamatergic forebrain neurons expressing Cre under the Emx1 promoter (BsnEmx1 cKO), and (iii) dopaminergic neurons expressing DAT-driven Cre (BsnDAT). MethodsSingle-photon emission computed tomography (SPECT) imaging of cerebral blood flow (CBF) was employed to assess in vivo brain-wide activation patterns in the cKO mice and corresponding control animals with wildtype Bsn genes. A cortex-dependent learning task to discriminate frequency-modulated tones was then used to evaluate the cognitive abilities of the different cKO lines. ResultsMarked reduction of brain activity was found in various cortical areas and the basolateral amygdala of BsnDlx5/6 cKO mice, while patches of increased activity were detected in the dorsal striatum. BsnEmx1 cKO mice, in contrast, display increased brain activity in many cortical areas. Only minor changes in CBF were detected in BsnDAT cKO mice. Concerning auditory discrimination learning BsnDlx5/6 cKO mice were severely impaired, although they responded to stimuli normally. On the other hand, BsnEmx1 cKO mice acquired the task more efficiently reaching maximum performance levels faster than control animals. Surprisingly, BsnDAT cKO mice did not differ in their behavior from the control group. ConclusionsOur data suggest that absence of Bassoon from presynapses of GABAergic interneurons expressing Dlx5/6 gene during development results in severe neurological symptoms and associated dysfunctions. Instead, network changes associated with Bassoon deficiency at glutamate release sites of excitatory forebrain neurons, even seem to have an enhancing effect on learning. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC="FIGDIR/small/690204v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@a5de5eorg.highwire.dtl.DTLVardef@1a9eeadorg.highwire.dtl.DTLVardef@174ccd1org.highwire.dtl.DTLVardef@132d92b_HPS_FORMAT_FIGEXP M_FIG C_FIG