Fast-spiking parvalbumin-positive interneurons in brain physiology and Alzheimer's disease

Abstract

Fast-spiking parvalbumin (PV) interneurons are inhibitory interneurons with unique morphological and functional properties that allow them to precisely control local circuitry, brain networks and memory processing. Since the discovery in 1987 that PV is expressed in a subset of fast-spiking GABAergic inhibitory neurons, our knowledge of the complex molecular and physiological properties of these cells has been expanding. In this review, we highlight the specific properties of PV neurons that allow them to fire at high frequency and with high reliability, enabling them to control network oscillations and shape the encoding, consolidation and retrieval of memories. We next discuss multiple studies reporting PV neuron impairment as a critical step in neuronal network dysfunction and cognitive decline in mouse models of Alzheimer's disease (AD). Finally, we propose potential mechanisms underlying PV neuron dysfunction in AD and we argue that early changes in PV neuron activity could be a causal step in AD-associated network and memory impairment and a significant contributor to disease pathogenesis.

Fig. 1. PV neurons control network oscillations.

A PV neurons (blue) in the CA1 region of the hippocampus control network activity via feedback inhibition (1), feedforward inhibition (2) and autaptic self-inhibition (3). Their fast-spiking properties and fast GABA release onto pyramidal neurons (gray) are due to the expression of specific ion channels and calcium sensors. Nav1.1 sodium and Kv1 and Kv3 potassium channel subunits enable high frequency firing of PV neuron in response to depolarizing currents while HCN channels facilitate action potential propagation. P/Q-type calcium channel subunits and synaptotagmin 2 allow for precise GABA release resulting in accurately timed inhibitory postsynaptic currents in pyramidal neurons. B CA1 PV and pyramidal neuron spikes are time-locked with theta-nested gamma oscillations during learning and memory. The oscillatory wave depends on PV neurons firing periodically at gamma frequencies in the trough of the theta wave followed by pyramidal neuron firing at the peak of the theta wave. C During rest and sleep, high frequency PV neuron firing is phase-coupled to the oscillatory cycle of sharp-wave ripples oscillations.

Fig. 2. Timeline of major events in the development and maturation of PV interneurons.

Synaptogenesis and myelination occur in early postnatal development. Microglia subsequently shape inhibitory synapses and strengthen connectivity between PV neurons and their postsynaptic targets. Next, PV neuron axons are further refined and become fully myelinated, and there is increased expression of ion channels required for fast spiking, enabling PV neurons to achieve precise temporal and spatial control of microcircuits. This postnatal pattern of PV neuron maturation is causally linked to an increase in working memory and cognitive flexibility that is observed until early adulthood.

Fig. 3. A potential role for PV neurons in shaping memory-specific neuronal ensembles.

A PV neurons shape memory engrams by preventing excessive activation of pyramidal cells. They thus control the size of an engram and contribute to the storage and recall of specific memories. B When PV neuron activity is increased, pyramidal cells receive too much inhibition during memory allocation, and smaller engrams are formed. This would hypothetically result in weaker memories. C When PV neuron activity is decreased, too many pyramidal cells are recruited in memory engrams, which would hypothetically lead to larger engrams and generalization of memories. It is important to note that in addition to PV cells, other interneurons have also been shown to play a crucial role in shaping neuronal memory ensembles (see main text for details).

Fig. 4. A hypothetical pathogenic mechanism for neuronal network changes in AD based on PV neuron dysfunction.

Neuronal hyperexcitability and network dysfunction are commonly observed in AD patients and in mouse models of AD. Taken together, published data seem to support a model in which interneurons, in particular PV interneurons, play a key role. Early in disease pathogenesis, before any significant aggregation of Aβ into plaques, soluble Aβ causes an aberrant increase in the excitability of PV cells and a corresponding increase in network inhibition. This is accompanied by an increase in perineuronal nets around PV cells, possibly to support the increased energy demand due to higher activity. Pyramidal cells at this stage seem unaffected, possibly because they are less vulnerable or less sensitive to Aβ toxicity. At a later stage, pyramidal cells also show increased excitability, possibly as a homeostatic response to restore excitation/inhibition balance. Increasing Aβ concentrations and Aβ aggregation may contribute to the increased excitability of pyramidal cells. Finally, PV cells become hypoactive while pyramidal cells remain hyperexcitable due to increasing Aβ pathology, resulting in an overall network hyperexcitability. The reduced activity of PV neurons is linked to a reduced expression and/or function of Nav1.1 and Kv3 channels. This stage is supported by both patient and mouse data showing reduced gamma oscillations and increased epileptic activity.