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Jonathon Burnside

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Aug 3, 2024, 1:44:49 PM8/3/24

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Due to a remarkably short action potential (AP) duration and refractory period, fast-spiking PV neurons are capable of generating high-frequency trains of APs when artificially stimulated as well as in freely behaving animals [2, 3]. Recordings from PV neurons in brain slices have shown that APs are initiated close to the soma and propagate with high reliability [4]. High frequency AP firing is followed by extremely fast GABA release in the order of a few milliseconds [5], at PV interneuron axon terminals, which is critical for the proper temporal control of microcircuits [5]. These unique firing and signaling properties depend on the expression of specific ion channels and their distinct subcellular localization (Fig. 1A, for an outstanding review on the molecular, cellular, and network properties of PV interneurons see [2]). The Nav1.1 voltage-gated sodium channel subunit is mainly expressed on axons of fast-spiking PV neurons, allowing for rapid AP propagation and enabling high-frequency firing with very little propagation failure [4]. Other key players in PV neuron firing are Kv1 and Kv3 voltage-gated potassium channel subunits [6]. Kv3 channels, expressed predominantly in fast-spiking PV neurons, have a high activation threshold and rapid deactivation kinetics, resulting in fast repolarization and short AP duration [7]. The short duration of the AP and the fast deactivation of Kv3 channels after spike repolarization enable rapid recovery following each AP, thus contributing to the fast-spiking profile [2, 7, 8]. Kv3 channels are found at the soma of PV neurons, but are also highly expressed at axon terminals, facilitating fast GABA release at synaptic sites [7, 9, 10]. Kv1 channels, on the other hand, are present in the axon initial segment and soma of PV neurons, and are responsible for controlling AP firing threshold and are necessary for a persistent potentiation of PV neuron excitability [6, 11]. A more recent study has confirmed the role for the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in fast AP signaling [12, 13]. In addition to modulating neuronal excitability, this study revealed that HCN channels enhance AP initiation during sustained firing and facilitate the propagation of APs [12]. HCN channels are activated by hyperpolarization and are permeable to K+ and Na+, leading to a positive shift in cell resting membrane potential and thereby enabling faster membrane potential kinetics. HCN channels were also recently linked to fast electrical reactivity of fast-spiking cells in the human neocortex [14].

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.

PV neurons also express high levels of P/Q-type calcium channels, which contribute to the fast and precise release of GABA from PV axon terminals into the synaptic cleft [5, 15, 16]. Furthermore, the presynaptic calcium sensor synaptotagmin 2, which is predominantly found in PV neurons and exhibits the fastest calcium-binding kinetics of all synaptotagmins, is thought to also contribute to fast GABA release from PV neurons [17, 18]. Another distinctive feature of PV interneurons is their activity-dependent myelination, as other local interneurons are rarely myelinated [19]. This was recently shown to increase AP conduction velocity and facilitate feedforward inhibition in the cortex [20, 21]. Finally, fast-spiking PV neurons are the only interneurons reported to have autapses, synapses made by a neuron onto itself, both in humans and mice. These autapses have been suggested to increase reliability of fast inhibition by PV neurons and to allow modulation of network activity, and they have been reported in various brain regions [22,23,24]. In conclusion, unique molecular adaptations allow PV neurons to rapidly transmit electrical and chemical signals and control network activity in a very precise manner.

PV neurons only reach their full electrophysiological and morphological maturation after a defined critical juvenile period (Fig. 2). Following myelination and the appearance of synaptic contacts in the first postnatal week, extensive refinement of PV neuron inhibitory synapses is observed during the weeks thereafter [25, 26]. PV axons display remodeling, including the removal of distal axonal branches and an increase in uniform axonal path lengths and myelination [26]. Studies have suggested that inhibitory PV synapse maturation and refinement depend on critical communication between microglial cells, PV neurons and their post-synaptic targets [27, 28]. In fact, removal of GABA-B1 receptors from microglia during development lead to a decrease in inhibitory synapses in adulthood and impaired GABAergic transmission in the somatosensory cortex of mice [25]. Also, microglia were found to be necessary for bouton maintenance on PV-expressing axo-axonic cells [29]. Moreover, the unique firing properties of PV neurons develop in an activity-dependent manner [30, 31] and presynaptic input onto PV neurons is critical for their maturation and functional integration into networks [32, 33]. The developmental refinement of PV neuron connectivity underlies important mechanisms of learning and plasticity that persist into adulthood [34,35,36,37,38]. Specifically, PV neuron maturation state has been associated with critical period-type plasticity [34,35,36, 39,40,41].

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.

Full electrophysiological maturation of PV neurons further depends on the extent of expression of the above-mentioned ion channels. Kv3 channels, for instance, double their expression level from P18 to P30 [42]. Importantly, between postnatal week 2 and 4, PV neurons reduce their input resistance, resting membrane potential, AP duration and latency, and AP propagation time and release period by more than 50%, while rheobase (i.e., the minimum amount of current required to induce AP firing), sag ratio (i.e., the ratio between the steady state decrease in the voltage and the largest decrease in voltage following a hyperpolarizing current step) and firing frequency are drastically increased [42, 43]. Notably, aberrant PV neuron maturation has been suggested as a key player in the pathogenesis of neurodevelopmental disorders such as schizophrenia (see review [19]).

In addition to their specific molecular attributes, PV interneurons also have distinctive morphological features that allow them to control microcircuits. Their long dendrites cross multiple layers in the hippocampus and in the cortex [2] and they receive excitatory input from many different areas, such as from entorhinal cortex and medial septum in the hippocampus or from thalamic inputs in the cortex, as well as from a vast number of local excitatory neurons across different hippocampal areas or cortical layers [1, 44,45,46,47]. While pyramidal neurons in the hippocampus have on average 1.6 spines/μm, PV neurons receive 3.3 excitatory inputs/μm of dendritic shaft [48]. In total, PV neurons receive ten times more excitatory than inhibitory inputs. Conversely, paired recordings from PV and pyramidal neurons revealed that a single PV interneuron projects to almost all local pyramidal neurons within its vicinity [49]. In the hippocampus, one PV neuron contacts approximately 1100 pyramidal neurons with on average six synaptic contacts per neuron [48]. These very specific input and output characteristics allow PV neurons to provide precise feedforward and feedback inhibitory control in hippocampal and cortical microcircuits (Fig. 1A). Accordingly, PV interneurons are crucial for the maintenance of excitation/inhibition (E/I) balance [11, 50,51,52,53,54,55,56]. In addition to controlling homeostatic balance at baseline, the precise firing of pyramidal neurons following sensory stimulation also depends on PV neuron-mediated feed-forward inhibition [50, 57,58,59]. Hippocampal place cell activity, for instance, is generated through an interaction between dendritic excitation by pyramidal cells and perisomatic inhibition by PV interneurons, and optogenetic silencing of PV interneurons increases the firing rate of pyramidal neurons in their place fields during behavior [60]. Entorhinal cortex stellate excitatory cells were shown to be mainly connected via PV interneurons, and this inhibitory microcircuit was found to shape grid-cell firing patterns [61]. By dynamically controlling the firing activity of excitatory cells, PV neurons also play a role in defining the exact population size of pyramidal neurons activated in a specific circuit [37, 62, 63]. This property of PV neurons seems indispensable in the recruitment of defined neuronal ensembles that underlie memory formation and storage (further discussed below).