Absence of GluN2A in hippocampal CA1 neurons leads to altered dendritic structure and reduced frequency of miniature excitatory synaptic events.

GluN2A is a NMDA receptor subunit postulated as important for learning and memory. In humans, heterozygous loss of function variants in the gene encoding it () increase the risk of epilepsy, intellectual disability and schizophrenia. Haploinsufficient mouse models show electrophysiological abnormalities and thus to improve and widen understanding of the pathogenesis of -associated disorders in humans, this study aimed to assess the impact of absence and haploinsufficiency on core neuronal and synaptic properties in genetically modified rats. Electrophysiological whole-cell current- and voltage-clamp recordings were made from CA1 pyramidal neurons in acute hippocampal slices from wild-type and heterozygous ( ) and homozygous ( ) knock out rats aged postnatal day 27-34. While reduced levels or absence of GluN2A did not affect neuronal excitability or intrinsic membrane properties in both and rats, we found a reduced frequency of miniature excitatory post synaptic currents and a reduced density of proximal dendrites suggestive of a reduced number of excitatory synapses. Recordings from CA1 neurons in slices prepared from and rats revealed there was a reduced ratio of the current mediated by NMDA receptors compared to AMPA receptors, while in recordings, there was a slowing of the decay time-constant of the NMDA receptor-mediated excitatory postsynaptic currents. Moreover, neither summation of sub-threshold excitatory postsynaptic potentials nor summation of supra-threshold excitatory postsynaptic potentials to initiate action potential firing in CA1 pyramidal neurons indicated any dependence on GluN2A. We conclude that reduced levels of GluN2A alters the kinetics of NMDA receptor-mediated synaptic events and dendritic structure of CA1 neurons, but do not affect several other core neuronal functions. These relatively subtle changes are consistent with the largely intact neural functioning of the majority of humans carrying loss of function variants. Further research could explore whether the changes in synaptic properties we observed contribute to alterations in higher level circuit dynamics and computation, which may manifest as disorders of cognition and excitability in humans.