Multivariate synaptic and behavioral profiling reveals new developmental endophenotypes in the prefrontal cortex

Abstract

The postnatal maturation of the prefrontal cortex (PFC) represents a period of increased vulnerability to risk factors and emergence of neuropsychiatric disorders. To disambiguate the pathophysiological mechanisms contributing to these disorders, we revisited the endophenotype approach from a developmental viewpoint. The extracellular matrix protein reelin which contributes to cellular and network plasticity, is a risk factor for several psychiatric diseases. We mapped the aggregate effect of the RELN risk allele on postnatal development of PFC functions by cross-sectional synaptic and behavioral analysis of reelin-haploinsufficient mice. Multivariate analysis of bootstrapped datasets revealed subgroups of phenotypic traits specific to each maturational epoch. The preeminence of synaptic AMPA/NMDA receptor content to pre-weaning and juvenile endophenotypes shifts to long-term potentiation and memory renewal during adolescence followed by NMDA-GluN2B synaptic content in adulthood. Strikingly, multivariate analysis shows that pharmacological rehabilitation of reelin haploinsufficient dysfunctions is mediated through induction of new endophenotypes rather than reversion to wild-type traits. By delineating previously unknown developmental endophenotypic sequences, we conceived a promising general strategy to disambiguate the molecular underpinnings of complex psychiatric disorders and for the rational design of pharmacotherapies in these disorders.

Reelin-Haploinsufficiency Disrupts the Developmental Trajectory of the E/I Balance in the Prefrontal Cortex

“…These developmental epochs match our recent report studying the effect of reelin-haploinsufficiency on the maturation of deep layer PrPFC excitatory synapses (Iafrati et al, 2016). Here, we also focused on layer 5/6 pyramidal neurons, one of the main output cells of the PrPFC microcircuit.…”

“…Additionally, previous data from our laboratory have shown that reelin is necessary for the maturation of NMDA receptors (Sinagra et al, 2005; Groc et al, 2007; Campo et al, 2009). More recently, we have shown that spine density, excitatory synaptic transmission and plasticity of prefrontal pyramidal neurons as well as cognitive traits are altered during the postnatal maturation of the reelin-haploinsufficient heterozygous reeler mice (HRM) prefrontal cortex (PFC) (Iafrati et al, 2014; Iafrati et al, 2016). We showed that reelin is necessary for the correct structural and functional maturation of deep layer excitatory synapses of the prelimbic area of the PFC (PrPFC) and that reelin happloinsufficiency delineates prefrontal endophenotypes thus identifying reelin as a risk gene for PFC maturational cognitive deficits (Iafrati et al, 2014; Iafrati et al, 2016).…”

“…More recently, we have shown that spine density, excitatory synaptic transmission and plasticity of prefrontal pyramidal neurons as well as cognitive traits are altered during the postnatal maturation of the reelin-haploinsufficient heterozygous reeler mice (HRM) prefrontal cortex (PFC) (Iafrati et al, 2014; Iafrati et al, 2016). We showed that reelin is necessary for the correct structural and functional maturation of deep layer excitatory synapses of the prelimbic area of the PFC (PrPFC) and that reelin happloinsufficiency delineates prefrontal endophenotypes thus identifying reelin as a risk gene for PFC maturational cognitive deficits (Iafrati et al, 2014; Iafrati et al, 2016). Despite these advancements, and apart from studies reporting alterations in GABAergic markers and reduced number of purkinje cells in HRM (Hadj-Sahraoui et al, 1996; Biamonte et al, 2009; Nullmeier et al, 2011) as well as the correlation between firing properties and neurochemical identity of reelin-expressing interneurons (Pohlkamp et al, 2014), the role of reelin in the maturation and plasticity of GABAergic connectivity has not been investigated.…”

“…One distinctive feature of the PFC is its protracted maturation through early adulthood (Gogtay et al, 2004) characterized by connectivity refinement in parallel to maturation of cognitive abilities (van Eden et al, 1990; Luna et al, 2001). This extended period of maturation constitutes a sensitive period of increased vulnerability to injuries leading to development of neurophychiatric disorders (Lewis, 1997; McEwen and Morrison, 2013; Iafrati et al, 2016; Labouesse et al, 2016). Several studies suggest that alterations of postnatal PFC maturation may contribute to the development of psychiatric diseases including depression, addiction, ASD and schizophrenia (Lewis, 1997; Raedler et al, 1998; Iafrati et al, 2016).…”

“…This extended period of maturation constitutes a sensitive period of increased vulnerability to injuries leading to development of neurophychiatric disorders (Lewis, 1997; McEwen and Morrison, 2013; Iafrati et al, 2016; Labouesse et al, 2016). Several studies suggest that alterations of postnatal PFC maturation may contribute to the development of psychiatric diseases including depression, addiction, ASD and schizophrenia (Lewis, 1997; Raedler et al, 1998; Iafrati et al, 2016). Neuronal deficits associated to these disorders could include reduced elaboration of inhibitory connectivity leading to altered excitation–inhibition (E/I) balance in the PFC (Insel, 2010).…”