Parvalbumin deficiency affects network properties resulting in increased susceptibility to epileptic seizures

Abstract

Networks of GABAergic interneurons are of utmost importance in generating and promoting synchronous activity and are involved in producing coherent oscillations. These neurons are characterized by their fast-spiking rate and by the expression of the Ca 2+ -binding protein parvalbumin (PV). Alteration of their inhibitory activity has been proposed as a major mechanism leading to epileptic seizures and thus the role of PV in maintaining the stability of neuronal networks was assessed in knockout (PVÀ/À) mice. Pentylenetetrazole induced generalized tonic -clonic seizures in all genotypes, but the severity of seizures was significantly greater in PVÀ/À than in PV+/+ animals. Extracellular single-unit activity recorded from over 1000 neurons in vivo in the temporal cortex revealed an increase of units firing regularly and a decrease of cells firing in bursts. In the hippocampus, PV deficiency facilitated the GABA A ergic current reversal induced by high-frequency stimulation, a mechanism implied in the generation of epileptic activity. We postulate that PV plays a key role in the regulation of local inhibitory effects exerted by GABAergic interneurons on pyramidal neurons. Through an increase in inhibition, the absence of PV facilitates synchronous activity in the cortex and facilitates hypersynchrony through the depolarizing action of GABA in the hippocampus.

Visual thalamocortical circuits in parvalbumin-deficient mice

“…Also, in striatal fast-spiking interneurons of PVKO mice, the increased excitability is reverted close to the WT situation by adding EGTA to the patch pipette (Orduz et al, in press). Furthermore, PV expression in the mouse brain starts relatively late commencing between postnatal day 10 (P10) and P14 as evidenced in the neocortex (del Río et al, 1994) and in the cerebellum (Collin et al, 2005); not surprisingly, no principal differences in the distribution and morphology of "PV-ir" neurons in PVKO mice are observed, neither in the hippocampus (Vreugdenhil et al, 2003) nor the cortex (Schwaller et al, 2004). All these results strongly support our hypothesis that changes observed in PVKO mice are mostly the direct result of PV's absence, rather than caused by compensation mechanisms in these mice.…”

“…The acceleration of the early phase of [Ca 2+ ] i decay associated to PV activity limits or slows down the buildup of residual [Ca 2+ ] i in presynaptic terminals, thus affecting short-term plasticity (Caillard et al, 2000;Vreugdenhil et al, 2003). Several observations indicate that a decrease in the expression of PV is likely to lead to behavioral and neurochemical alterations that have been associated to epileptic seizure susceptibility (Marco et al, 1997;Schwaller et al, 2004;Farré-Castany et al, 2007), schizophrenia (Pinault, 2011;Lewis et al, 2012) and autism spectrum disorder (Oblak et al, 2011). The hypothesis is that elimination of PV produces alterations of brain development during specific periods of pre or postnatal life (Heizmann and Braun, 1992).…”

“…Nowadays PV knockout (PVKO) mice represent an essential animal model to study the effects of absence of PV (Schwaller, 2012b). Parvalbumin is highly expressed in GABAergic neurons (Celio, 1990) and the reactivity for the perineuronal net marker around GABAergic neurons confirmed that GABAergic neurons are still viable in PVKO mice (Schwaller et al, 2004). Specific parvalbumin immunoreactivity (PV-ir) was identified within subpopulations of ganglion and amacrine cells of the mouse retina (Endo et al, 1986;Sanna et al, 1993;Kim and Jeon, 2006).…”

Differences in locomotor behavior revealed in mice deficient for the calcium-binding proteins parvalbumin, calbindin D-28k or both

“…Closer inspection of PV−/−, CB−/− and PV−/−CB−/− mice revealed significant functional alterations at cortical, hippocampal and cerebellar levels (for a review on the cerebellum, see [4]). Electrophysiological recordings of cortical, hippocampal and cerebellar sites in PV−/− mice showed important modifications in the function of the inhibitory systems [14,16,17,35]. Moreover, direct evidence that endogenous CaBPs play an important role in the cerebellar physiology was provided by behavioral analysis investigated in CB−/− mice and more recently in mice lacking the closely related protein calretinin.…”

“…Previous work reported several physiological alterations at neuronal and muscular levels in these animals. PV−/− mice revealed electrophysiological alterations associated with PV-expressing cortical neurons [14], cerebellar stellate and basket cells [15,16] and hippocampal PV-immunoreactive interneurons [17]. CB−/− mice showed impairment in motor coordination associated with altered synaptic Ca 2+ transients in Purkinje cell dendrites [12].…”