The ascending median raphe projections are mainly glutamatergic in the mouse forebrain.
The median raphe region (MRR) is thought to be serotonergic and plays an important role in the regulation of many cognitive functions. In the hippocampus (HIPP), the MRR exerts a fast excitatory control, partially through glutamatergic transmission, on a subpopulation of GABAergic interneurons that are key regulators of local network activity. However, not all receptors of this connection in the HIPP and in synapses established by MRR in other brain areas are known. Using combined anterograde tracing and immunogold methods, we show that the GluN2A subunit of the NMDA receptor is present in the synapses established by MRR not only in the HIPP, but also in the medial septum (MS) and in the medial prefrontal cortex (mPFC) of the mouse. We estimated similar amounts of NMDA receptors in these synapses established by the MRR and in local adjacent excitatory synapses. Using retrograde tracing and confocal laser scanning microscopy, we found that the majority of the projecting cells of the mouse MRR contain the vesicular glutamate transporter type 3 (vGluT3). Furthermore, using double retrograde tracing, we found that single cells of the MRR can innervate the HIPP and mPFC or the MS and mPFC simultaneously, and these double-projecting cells are also predominantly vGluT3-positive. Our results indicate that the majority of the output of the MRR is glutamatergic and acts through NMDA receptor-containing synapses. This suggests that key forebrain areas receive precisely targeted excitatory input from the MRR, which is able to synchronously modify activity in those regions via individual MRR cells with dual projections.
Laboratory of Cerebral Cortex Research, Institute of Experimental Medicine Hungarian Academy of Sciences, Budapest, 1083, Hungary.|János Szentágothai Doctoral School of Neurosciences, Semmelweis University, Budapest, 1085, Hungary.
András
A
Szőnyi
Laboratory of Cerebral Cortex Research, Institute of Experimental Medicine Hungarian Academy of Sciences, Budapest, 1083, Hungary.
Márton I
MI
Mayer
Laboratory of Cerebral Cortex Research, Institute of Experimental Medicine Hungarian Academy of Sciences, Budapest, 1083, Hungary.
Csaba
C
Cserép
Laboratory of Cerebral Cortex Research, Institute of Experimental Medicine Hungarian Academy of Sciences, Budapest, 1083, Hungary.
Virág T
VT
Takács
Department of Anatomy, Hokkaido University School of Medicine, Sapporo, 060-8638, Japan.
Masahiko
M
Watanabe
Laboratory of Cerebral Cortex Research, Institute of Experimental Medicine Hungarian Academy of Sciences, Budapest, 1083, Hungary.
Tamás F
TF
Freund
Laboratory of Cerebral Cortex Research, Institute of Experimental Medicine Hungarian Academy of Sciences, Budapest, 1083, Hungary. nyiri.gabor@koki.mta.hu.
Gábor
G
Nyiri
D000818:Animals; D005971:Glutamates / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism; D016548:Prosencephalon / Q000166:cytology / Q000378:metabolism*; D011903:Raphe Nuclei / Q000166:cytology / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D050496:Vesicular Glutamate Transport Proteins / Q000378:metabolism
D005971:Glutamates; D016194:Receptors, N-Methyl-D-Aspartate; D050496:Vesicular Glutamate Transport Proteins
GABAergic interneurons; Hippocampus; Immunohistochemistry; Medial septum; Median raphe; Mouse; NMDA receptor; Non-serotonergic; Prefrontal cortex; Vesicular glutamate transporter type 3; vGluT3