Overexpression ofDyrk1A, a Down Syndrome Candidate, Decreases Excitability and Impairs Gamma Oscillations in the Prefrontal Cortex

Abstract

The dual-specificity tyrosine phosphorylation-regulated kinase DYRK1A is a serine/threonine kinase involved in neuronal differentiation and synaptic plasticity and a major candidate of Down syndrome brain alterations and cognitive deficits. DYRK1A is strongly expressed in the cerebral cortex, and its overexpression leads to defective cortical pyramidal cell morphology, synaptic plasticity deficits, and altered excitation/inhibition balance. These previous observations, however, do not allow predicting how the behavior of the prefrontal cortex (PFC) network and the resulting properties of its emergent activity are affected. Here, we integrate functional, anatomical, and computational data describing the prefrontal network alterations in transgenic mice overexpressing Dyrk1A (TgDyrk1A). Using in vivo extracellular recordings, we show decreased firing rate and gamma frequency power in the prefrontal network of anesthetized and awake TgDyrk1A mice. Immunohistochemical analysis identified a selective reduction of vesicular GABA transporter punctae on parvalbumin positive neurons, without changes in the number of cortical GABAergic neurons in the PFC of TgDyrk1A mice, which suggests that selective disinhibition of parvalbumin interneurons would result in an overinhibited functional network. Using a conductance-based computational model, we quantitatively demonstrate that this alteration could explain the observed functional deficits including decreased gamma power and firing rate. Our results suggest that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of Down syndrome.

Altered Hippocampal-Prefrontal Neural Dynamics in Mouse Models of Down Syndrome

“…Finally, previous studies of transgenic mouse models of DS have led to the proposal that the overexpression of Dyrk1a (and thus an increased dosage of the DYRK1A protein) makes a critical contribution to neurological and behavioral abnormalities by shifting the excitation/inhibition balance toward inhibition, for example (Ruiz-Mejias et al, 2016;Souchet et al, 2014). The Dyrk1a gene maps to the Mmu16 region of Hsa21 and so is duplicated within the Dp1Tyb strain.…”

“…The current global population of people with DS is estimated at 6 million (Hanney et al, 2012), and prevalence is rising, primarily due to an increase in maternal age (a major risk factor for DS) and increased life expectancy in people with DS, resulting from reduced infant mortality rates and improved access to health-care (Loane et al, 2013;Sherman et al, 2007;Wu and Morris, 2013). DS is characterized by intellectual disability (Grieco et al, 2015;Lott and Dierssen, 2010) and prominent impairments in planning, decision-making, and memory function (Clark et al, 2017;Grieco et al, 2015;Lanfranchi et al, 2010;Lavenex et al, 2015;Pennington et al, 2003;Rowe et al, 2006), which likely arise from functional abnormalities of the hippocampus and medial prefrontal cortex (mPFC; Anderson et al, 2013;Lott and Dierssen, 2010;Nadel, 2003;Nelson et al, 2005;Pennington et al, 2003;Rowe et al, 2006;Ruiz-Mejias et al, 2016). Increased dosages of single genes in Hsa21, such as Dyrk1A, have been proposed to account for many of the alterations in neural development and abnormal phenotypes associated with DS and are thus targets for therapy development (Duchon and Herault, 2016).…”

“…In combination, these three mouse strains are triplicated for almost all the genes on Hsa21. We hypothesized that these trisomic mice might exhibit distinct cognitive impairments, corresponding to distinct alterations in oscillatory activity patterns within the hippocampus and mPFC (Anderson et al, 2013;Ruiz-Mejias et al, 2016). Hence, we carried out simultaneous local field potential (LFP) recordings from those regions while mice performed a canonical test of spatial working memory-the spontaneous alternation task-which, importantly, can dissociate mnemonic function (i.e., alternation success; Deacon and Rawlins, 2006;Sarnyai et al, 2000;Wenk, 2001) from planning and decisionmaking processes (i.e., trial latency; Bizon et al, 2012;Pioli et al, 2014).…”

Modulation of cortical slow oscillatory rhythm by GABABreceptors: an experimental and computational study

“…On the other hand, low levels of synchronization are observed during alert or attentional states, short-term memory tasks, or movements, at local cortical areas (Stancák and Pfurtscheller, 1996;Klimesch et al, 2007;Okun and Lampl, 2008;Doesburg et al, 2010). Malfunctions controlling neural synchronization at different oscillatory frequencies are related to several neurological diseases such as Alzheimer's (Busche et al, 2015;Castano-Prat et al, 2019), early aging (Castano-Prat et al, 2017), Parkinson's (Little and Brown, 2014), autism (Rubenstein and Merzenich, 2003), Williams Beuren syndrome (Dasilva et al, 2019), or Down Syndrome (Ruiz-Mejias et al, 2016), among others. Although the control of the degree of synchronization of neural activity is essential in order to understand normal and pathological brain function, there are still open questions regarding the basic mechanisms underlying network synchronization.…”

Speed hysteresis and noise shaping of traveling fronts in neural fields: role of local circuitry and nonlocal connectivity

“…This multiscale organization of cortical waves calls for understanding the theoretical characterization of the phenomenon making elusive the interplay between network structure and spatiotemporal patterns of activity expressed1415. Unraveling the relationship between structure and function is crucial to address questions of wide interest, like the mechanistic roots of neurological disorders which are known to affect ongoing rhythmic wave production in sleeping and anesthetized brains1617.…”