Selective Postnatal Excitation of Neocortical Pyramidal Neurons Results in Distinctive Behavioral and Circuit Deficits in Adulthood

Abstract

In leading models of Autism Spectrum Disorder, and in human data, the efficacy of outgoing cortical connectivity transitions from overly exuberant to languid from early development to adulthood. This transition begs the question of whether the early enhancement in excitation might be a common driver, across etiologies, of these symptoms. We directly tested this concept by chemogenetically driving neuronal activity in neocortical neurons during postnatal days 4-14. Hyperexcitation of Emx1-, but not dopamine transporter-, parvalbumin-, or Dlx5/6-expressing neurons led to decreased social interaction and increased grooming activity in adult animals. In vivo optogenetic interrogation in adults revealed decreased baseline but increased stimulus-evoked firing rates of pyramidal neurons, impaired recruitment of inhibitory neurons and reduced cortico-striatal communication. These results directly support the prediction that changed firing in developing circuits irreversibly alters adult circuit function that leads to maladaptive changes in behaviors. This experimental approach offers a valuable platform to study the impact of disruption of developmental neural activity on the formation and function of adult neural circuits and behavior.

Prefrontal Cortex Development in Health and Disease: Lessons from Rodents and Humans

“…Unpublished results from our group suggest, for instance, that a protracted but subtle increase of PYRs II/III firing across the first two postnatal weeks results in long-term prefrontal microcircuit disruption and an excitation/inhibition (E/I) imbalance that worsens over time, equally leading to cognitive and social deficits [43]. Similar deficits have also been described in mouse models of autism spectrum disorder, which are characterized by increased prefrontal activity [54][55][56]. Another important piece of the puzzle is the role of inhibitory neurons in prefrontal development.…”

“…The downstream striatal response to excessive cortical activity is twofold: at the beginning of the first postnatal week, it induces striatal hyperactivity and hyperconnectivity in cortical-striatal circuits, whereas the contrary occurs towards the third postnatal week [55,73]. Further, according to preliminary results, selectively increasing the firing of pyramidal neurons from P4 to P14 leads to an imbalanced prefrontal network, decreased corticostriatal connectivity at adulthood, and behavioral abnormalities reminiscent of autism spectrum disorder [54]. On the flipside, transiently increasing the activity of D2 dopamine receptors in the mouse striatum impacts prefrontal development and PFC-dependent cognitive abilities [80].…”

The Logic of Developing Neocortical Circuits in Health and Disease

“…For instance, a protracted but subtle increase of L2/3 pyramidal cell firing across the first two postnatal weeks results in long-term prefrontal microcircuit disruption and E/I imbalance that worsens over time (Bitzenhofer et al, 2020b). Similar deficits have also been described in mouse models of autism spectrum disorder, which are characterized by increased prefrontal activity (Richter et al, 2019;Medendorp, 2020).…”

Chronic hM4Di-DREADD-Mediated Chemogenetic Inhibition of Forebrain Excitatory Neurons in Postnatal or Juvenile Life Does Not Alter Adult Mood-Related Behavior

“…A change in excitation-inhibition (E/I) balance during critical developmental time windows, with a shift towards enhanced excitation of forebrain pyramidal neurons and a commensurate reduction in inhibitory tone, has been posited to play a crucial role in the programming of life-long perturbations of mood-related behaviors in several neurodevelopmental disorder models (Fenton, 2015;Nelson and Valakh, 2015;Sohal and Rubenstein, 2019;Tatti et al, 2017;Yizhar et al, 2011). Indeed, hyperexcitation of Emx1positive neurons from P4-14 in the neocortex using either a non-invasive bioluminescent chemogenetics approach (Medendorp et al, 2021) or hM3Dq-DREADD mediated activation of CamKIIα-positive forebrain excitatory neurons from P2-P14 (Pati et al, 2020) resulted in enhanced anxiety-like behaviors and perturbed social behavior. An important experimental counterpart would be to increase inhibition in forebrain pyramidal neurons in these developmental windows, and address the influence on the emergence of mood-related behaviors.…”