Narp regulates homeostatic scaling of excitatory synapses on parvalbumin-expressing interneurons

Nptx2 is an activity-regulated protein that interacts with the extracellular domain of AMPA receptors to facilitate receptor clustering and insertion of GluR4 on the postsynaptic membrane of neurons, strengthening synaptic communication.

“Nptx2 is an activity-regulated protein that interacts with the extracellular domain of AMPA receptors to facilitate receptor clustering and insertion of GluR4 on the postsynaptic membrane of neurons, strengthening synaptic communication [24].”

NARP regulates PV neuron excitation through recruitment of glutamate (AMPA) receptors.

“neuronal pentraxin--2 (NARP) (Gu et al., 2013), which regulates PV neuron excitation through recruitment of glutamate (AMPA) receptors (Chang et al., 2010;Pelkey et al., 2015)”

Enhancing network activity increases excitatory transmission onto GABAergic interneurons.

“On the other hand, enhancing network activity does increase excitatory transmission onto GABAergic interneurons (Rutherford et al. 1998;Chang et al. 2010), which should promote the recruitment of additional inhibition when activity in a circuit increases.”

Interactions of ECM molecules with Narp complexes and integrins regulate AMPA and NMDA receptor subunit composition, synaptic clustering, and homeostatic synaptic scaling in GABAergic neurons.

“Notable examples are interactions of ECM molecules with ‘neuronal activity-regulated pentraxin’ (Narp) complexes and integrins, shown to regulate AMPA and NMDA receptor subunit composition, synaptic clustering and homeostatic synaptic scaling in GABAergic neurons (Campo et al., 2009; Chang et al., 2010; Cingolani et al., 2008; Dityatev et al., 2010; Frischknecht and Gundelfinger, 2012).”

The three NPTXs interact, directly or indirectly, with the N-terminal extracellular domain of AMPAR subunits (GluA1, GluA2, GluA3, and GluA4), via their conserved pentraxin domain.

“The three NPTXs interact, directly or indirectly, with the N-terminal extracellular domain of AMPAR subunits (GluA1, GluA2, GluA3 and GluA4), via their conserved pentraxin domain (Chang et al. 2010; Cho et al. 2008; Lee et al. 2017; Sia et al. 2007; Suzuki et al. 2020).”

Under physiological conditions, NPTX2 is mainly secreted from the pre-synaptic terminal into the synapses.

“Under physiological conditions, NPTX2 is mainly secreted from the pre-synaptic terminal into the synapses (Chang et al. 2010; Reti et al. 2002).”

The NPTX complex acts as a trans-synaptic signalling molecule, regulating the activity of neurotransmitter receptors at excitatory synapses.

“The NPTX complex acts as trans-synaptic signalling molecule, regulating the activity of neurotransmitter receptors at excitatory synapses.”

NPTXs are enriched at excitatory glutamatergic synapses of pyramidal neurons onto parvalbumin interneurons in the mice hippocampus.

“NPTXs are enriched at excitatory glutamatergic synapses of pyramidal neurons onto parvalbumin (PV) interneurons in the mice hippocampus (Chang et al. 2010)”

The dense perineuronal net characteristic of PV interneurons is required to stabilise NPTX2 in the synaptic cleft at these synapses.

“The dense perineuronal net (proteoglycan network structure on the cell surface), characteristic of PV interneurons (Carceller et al. 2020; Härtig et al. 1999), is required to stabilise NPTX2 in the synaptic cleft at these synapses (Chang et al. 2010).”

NPTX2 is an immediate early gene highly enriched at excitatory synapses onto PV-containing interneurons and promotes activity dependent accumulation of GluA4-containing AMPARs.

“NPTX2 is an immediate early gene highly enriched at excitatory synapses onto PV-containing interneurons and promotes activity dependent accumulation of GluA4-containing AMPARs (189).”

This regulation by NPTX2 critically dictates PV-containing interneuron recruitment to maintain E/I balance in the face of perturbations in network activity.

“This regulation by NPTX2 critically dictates PV-containing interneuron recruitment to maintain E/I balance in the face of perturbations in network activity (189).”