Afferent specific role of NMDA receptors for the circuit integration of hippocampal neurogliaform cells

R Chittajallu,M T Craig,C Fang,K A Pelkey,E Barksdale,G Akgül,J C Wester,X Q Yuan,C J Mcbain,D Collins,S Hunt

doi:10.1038/s41467-017-00218-y

Abstract

Appropriate integration of GABAergic interneurons into nascent cortical circuits is critical for ensuring normal information processing within the brain. Network and cognitive deficits associated with neurological disorders, such as schizophrenia, that result from NMDA receptor-hypofunction have been mainly attributed to dysfunction of parvalbumin-expressing interneurons that paradoxically express low levels of synaptic NMDA receptors. Here, we reveal that throughout postnatal development, thalamic, and entorhinal cortical inputs onto hippocampal neurogliaform cells are characterized by a large NMDA receptor-mediated component. This NMDA receptor-signaling is prerequisite for developmental programs ultimately responsible for the appropriate long-range AMPAR-mediated recruitment of neurogliaform cells. In contrast, AMPAR-mediated input at local Schaffer-collateral synapses on neurogliaform cells remains normal following NMDA receptor-ablation. These afferent specific deficits potentially impact neurogliaform cell mediated inhibition within the hippocampus and our findings reveal circuit loci implicating this relatively understudied interneuron subtype in the etiology of neurodevelopmental disorders characterized by NMDA receptor-hypofunction.

Highlights

Appropriate integration of GABAergic interneurons into nascent cortical circuits is critical for ensuring normal information processing within the brain
We demonstrate that NMDA receptor (NMDAR) are critical for developmental programs involved in appropriate expression of short-term plasticity, AMPA receptor (AMPAR) function and dendrite patterning
We initially focused on the major cohort of hippocampal neurogliaform cells (NGFCs) originating from the CGE and to this end employed the

Summary

Results

Developmental expression and ablation of NMDARs in CGE NGFCs. We initially focused on the major cohort of hippocampal NGFCs originating from the CGE and to this end employed the. Calculating the ratio of the evoked response across differing stimuli intensities upon SR and SLM afferent stimulation in each individual NGFC reveal that under WT conditions the SR afferents provide the dominant input that significantly shifts in favor of the SLM afferents upon NMDAR ablation (Fig. 7i) These data together demonstrate that NMDAR-hypofunction precipitates selective changes in the synaptic integration of an individual NGFC into the hippocampal circuitry dependent on whether the excitatory afferents arise from extra vs intra-hippocampal sources

Discussion

SLM input 20 ms

Methods