Publication Date:
2014-05-30
Description:
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 (NRXN1 and NRXN2) and CNTNAP2 (also known as CASPR2), 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 cells. Notably, other disease-associated genes such as BDNF and ERBB4 implicate specific interneuron synapses in psychiatric disorders. Consistent with this, cortical interneuron dysfunction has been linked to epilepsy, schizophrenia and autism. Using a microarray screen that focused upon synapse-associated molecules, we identified Cntnap4 (contactin associated protein-like 4, also known as Caspr4) 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 (gamma-aminobutyric acid producing) basket cells. Paradoxically, the loss of Cntnap4 augments midbrain dopaminergic release in the nucleus accumbens. In Cntnap4 mutant 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281262/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281262/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Karayannis, T -- Au, E -- Patel, J C -- Kruglikov, I -- Markx, S -- Delorme, R -- Heron, D -- Salomon, D -- Glessner, J -- Restituito, S -- Gordon, A -- Rodriguez-Murillo, L -- Roy, N C -- Gogos, J A -- Rudy, B -- Rice, M E -- Karayiorgou, M -- Hakonarson, H -- Keren, B -- Huguet, G -- Bourgeron, T -- Hoeffer, C -- Tsien, R W -- Peles, E -- Fishell, G -- NS30989/NS/NINDS NIH HHS/ -- NS50220/NS/NINDS NIH HHS/ -- P01 NS074972/NS/NINDS NIH HHS/ -- R01 DA033811/DA/NIDA NIH HHS/ -- R01 MH071679/MH/NIMH NIH HHS/ -- R01 NS030989/NS/NINDS NIH HHS/ -- R01 NS036362/NS/NINDS NIH HHS/ -- R01 NS050220/NS/NINDS NIH HHS/ -- R01 NS074972/NS/NINDS NIH HHS/ -- R01 NS081297/NS/NINDS NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2014 Jul 10;511(7508):236-40.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24870235" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antipsychotic Agents/pharmacology
;
Behavior, Animal/drug effects/physiology
;
Dopamine/*metabolism
;
Electrical Synapses/genetics/ultrastructure
;
Female
;
Genotype
;
Humans
;
Male
;
Membrane Proteins/*genetics/*metabolism
;
Mice
;
Nerve Tissue Proteins/*genetics/*metabolism
;
Polymorphism, Single Nucleotide
;
*Signal Transduction
;
Synaptic Transmission/*genetics
;
gamma-Aminobutyric Acid/*metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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