Sex-Specific Emergence of Prefrontal Pyramidal Neuron Dysfunction in a Developmental Model of Schizophrenia

Field: Neuroscience (Life Sciences)

The cognitive deficits associated with schizophrenia are among the strongest predictors of long-term disability and reduced quality of life. Despite their clinical implications, current treatment options provide limited relief for these symptoms, leaving patients with persistent impairments in executive function. Preclinical studies have linked cognitive impairment to disrupted activity in the medial prefrontal cortex (mPFC), a region essential for working memory and behavioral flexibility. Hypofunction of NMDA-type glutamate receptors (NMDARs) has been proposed to impair the stability of prefrontal network activity, contributing to cognitive and negative symptoms. While most studies have focused on inhibitory circuit disruption as a consequence of NMDAR hypofunction, pyramidal neurons are the principal excitatory cells in the mPFC and rely on NMDAR signaling for proper development and function, making them a likely site of vulnerability. Additionally, most models have focused exclusively on males, limiting their translational relevance given the clear clinical sex differences in disease progression. This dissertation uses a neonatal NMDAR hypofunction model to test whether early glutamatergic disruption alters intrinsic function in layer 5 pyramidal neurons, with a focus on characterizing sex-specific outcomes. In Chapter 2, we used whole-cell patch-clamp recordings in ex vivo mPFC slices to examine how early NMDAR hypofunction affects intrinsic physiology in male pyramidal neurons across development. No differences were observed in adolescence, while adult neurons showed increased excitability, reduced firing stability, elevated spike frequency adaptation, and disrupted maturation of membrane resistance. These findings indicate a delayed-onset, cell-intrinsic dysfunction that may impair the ability of prefrontal neurons to support cognitive processes such as working memory and behavioral flexibility. In Chapter 3, we used the same approach to assess whether early NMDAR hypofunction alters intrinsic physiology in female pyramidal neurons across development. No differences were observed in adolescence or adulthood, as MK-801-treated females exhibited stability excitability, consistent firing output, preserved spike adaptation, and unaltered passive membrane properties. These findings indicate that female neurons are resistant to early-life NMDAR hypofunction within the developmental window examined. Unlike males, females do not exhibit delayed-onset phenotype, and distinct maturational changes in control females raise the possibility that sex-specific patterns of physiological development contribute to this difference in treatment sensitivity. Chapter 4 synthesized findings from both sexes to evaluate how early NMDAR hypofunction alters intrinsic pyramidal neuron function in the mPFC. While treated males developed a delayed-onset excitability phenotype, females showed no such dysfunction. These outcomes support a sex-specific divergence in vulnerability to early glutamatergic disruption. To explain the absence of a phenotype in females, we proposed three possible models: true resistance, divergent physiological response, or delayed onset of dysfunction. Each possibility carries distinct implications for how neurodevelopmental insults shape circuit maturation and contribute to disease risk in females. Together, these findings highlight the importance of including sex as a biological variable in preclinical research and suggest that intrinsic neuronal mechanisms may underlie differential trajectories of cognitive vulnerability in schizophrenia.