Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission

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Although considerable evidence suggests that the chemical synapse is a lynchpin underlying affective disorders, how molecular insults differentially affect specific synaptic connections remains poorly understood. For instance, Neurexin 1a and 2 (NRXN1andNRXN2) andCNTNAP2(also known asCASPR2), all members of the neurexin superfamily of transmembrane molecules, have been implicated in neuropsychiatric disorders. However, their loss leads to deficits that have been best characterized with regard to their effect on excitatory cells1,2. Notably, other disease-associated genes such asBDNFandERBB4implicate specific interneuron synapses in psychiatric disorders3,4. Consistent with this, cortical interneuron dysfunction has been linked to epilepsy, schizophrenia and autism5,6. Using a microarray screen that focused upon synapse-associated molecules, we identifiedCntnap4(contactin associated protein-like 4, also known asCaspr4) as highly enriched in developing murine interneurons. In this study we show that Cntnap4 is localized presynaptically and its loss leads to a reduction in the output of cortical parvalbumin (PV)-positive GABAergic (γ-aminobutyric acid producing) basket cells. Paradoxically, the loss ofCntnap4augments midbrain dopaminergic release in the nucleus accumbens. InCntnap4mutant mice, synaptic defects in these disease-relevant neuronal populations are mirrored by sensory-motor gating and grooming endophenotypes; these symptoms could be pharmacologically reversed, providing promise for therapeutic intervention in psychiatric disorders.

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