NMDA Receptor Ablation on Parvalbumin-Positive Interneurons Impairs Hippocampal Synchrony, Spatial Representations, and Working Memory

Abstract

Activity of parvalbumin-positive hippocampal interneurons is critical for network synchronization but the receptors involved therein have remained largely unknown. Here we report network and behavioral deficits in mice with selective ablation of NMDA receptors in parvalbumin-positive interneurons (NR1(PVCre-/-)). Recordings of local field potentials and unitary neuronal activity in the hippocampal CA1 area revealed altered theta oscillations (5-10 Hz) in freely behaving NR1(PVCre-/-) mice. Moreover, in contrast to controls, in NR1(PVCre-/-) mice the remaining theta rhythm was abolished by the administration of atropine. Gamma oscillations (35-85 Hz) were increased and less modulated by the concurrent theta rhythm in the mutant. Positional firing of pyramidal cells in NR1(PVCre-/-) mice was less spatially and temporally precise. Finally, NR1(PVCre-/-) mice exhibited impaired spatial working as well as spatial short- and long-term recognition memory but showed no deficits in open field exploratory activity and spatial reference learning.

Highly Energized Inhibitory Interneurons are a Central Element for Information Processing in Cortical Networks

“…This notion has been underlined by elegant in vivo studies in mice showing that selective genetic modification of glutamate receptor subtypes in fast-spiking, PV þ interneurons strongly affects power and synchrony of gamma oscillations, together with impaired hippocampus-dependent cognitive functions. 50,51 56,86,98,112 This finding underlines the general principle of sparse coding by pyramidal cells, which has been suggested to provide an optimal trade-off between information processing and energy efficacy. 113,114 However, pyramidal cells comprise B85% of all neurons in the hippocampus proper, and even with sparse coding they are able to encode multiple representations of spatial and episodic memories.…”

“…8,16,19 Studies using transgenic mice with cell-specific deletion of glutamate receptor subunits show that synaptic excitation of fastspiking interneurons is required for generation of normal gamma oscillations in vivo. 50,51 The indispensable role of phasic GABAergic inhibition for generation of gamma oscillations is underlined by the fact that local field potentials in the gamma-frequency band are dominated by inhibitory postsynaptic potentials (IPSPs), rather than action potentials or excitatory postsynaptic potentials. 17,52,53 It is also in line with the models of gamma oscillations in neuronal networks that emphasize the importance of rhythmic and synchronous inhibition of both pyramidal cells and interneurons, which finally generates alternating phases of enhanced or decreased probability of spiking.…”

Dysconnectivity, large-scale networks and neuronal dynamics in schizophrenia

“…receptors have been shown to exert significant effects on gamma-band oscillations through modulating excitatory transmission on PV cells [24][25][26].…”

Estudos traducionais de neuropsiquiatria e esquizofrenia: modelos animais genéticos e de neurodesenvolvimento

“…Following the glutamate hypothesis, a mutant mouse strain has been created with a 90% reduction in NMDA receptor 1 (NR1) expression, resulting in social and sexual behavioural deficits and similar symptoms to the DAT knock out mouse. These include impaired circadian rhythm, memory and gating deficits, diminished reward learning and increased locomotion [104][105][106][107] . These symptoms could be reduced with haloperidol and clozapine treatment 104 .…”