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.

Placental transfer of Δ9-tetrahydrocannabinol (THC) during pregnancy has the potential to interfere with endogenous cannabinoid regulation of fetal nervous system development in utero. Here we examined the effect of maternal cannabinoid intake on mouse hippocampal interneurons largely focusing on cholecystokinin containing interneurons (CCK-INTs), a prominent cannabinoid subtype 1 receptor (CB1R) expressing neuronal population throughout development. Maternal treatment with THC or the synthetic CB1R agonist WIN55,212-2 (WIN) produced a significant loss of CCK-INTs in offspring. Further, residual CCK-INTs in animals prenatally treated with WIN displayed decreased dendritic complexity. Consistent with these anatomical deficits, pups born to cannabinoid treated dams exhibited compromised CCK-INT mediated feedforward and feedback inhibition. Moreover, pups exposed to WIN in utero lacked constitutive CB1R mediated suppression of inhibition from residual CCK-INTs, and displayed altered social behavior. Our findings add to a growing list of potential cell/circuit underpinnings that may underlie cognitive impairments in offspring of mothers that abuse marijuana during pregnancy.

Although Netos are considered auxiliary subunits critical for kainate receptor (KAR) function, direct evidence for their regulation of native KARs is limited. As Neto KAR regulation is GluK subunit/Neto isoform specific, such regulation must be determined in cell-type specific contexts. We demonstrate Neto1/2 expression in somatostatin- (SOM), cholecystokinin/cannabinoid receptor 1- (CCK/CB1), and parvalbumin- (PV) containing interneurons. KAR-mediated excitation of these interneurons is contingent upon Neto1 as kainate yields comparable effects in Neto2 knockouts and wildtypes, but fails to excite interneurons or recruit inhibition in Neto1 knockouts. In contrast, presynaptic KARs in CCK/CB1 interneurons are dually regulated by both Neto1 and Neto2. Neto association promotes tonic presynaptic KAR activation dampening CCK/CB1 interneuron output and loss of this brake in Neto mutants profoundly increases CCK/CB1 interneuron-mediated inhibition. Our results confirm that Neto1 regulates endogenous somatodendritic KARs in diverse interneurons and demonstrate Neto regulation of presynaptic KARs in mature inhibitory presynaptic terminals.