Age-dependent reorganization of behavioral and striatal function in Cntnap2 knockout mice

Mathieu Thabault, Cloé Fernandes-Gomes, Cloé Alcaraz, Anaïs Balbous, Pierre-Olivier Fernagut, Laurie Galvan
Neurobiology of Disease. 2026-10-01; 228: 107558
DOI: 10.1016/j.nbd.2026.107558

Thabault M(1), Fernandes-Gomes C(2), Alcaraz C(3), Balbous A(4), Fernagut PO(5), Galvan L(6).

Author information:
(1)Université de Poitiers, Inserm, Laboratoire de Neurosciences Expérimentales
et Cliniques, Poitiers, France; APC Microbiome Ireland, University College Cork,
Cork, Ireland; Department of Pharmacology and Therapeutics, University College
Cork, Cork, Ireland. Electronic address: .
(2)Université de Poitiers, Inserm, Laboratoire de Neurosciences Expérimentales
et Cliniques, Poitiers, France; Institut de Neurobiologie de la Méditerranée,
INSERM UMR1249, Marseille, France.
(3)NIMES UNIV, APSY-V, Nîmes, France.
(4)Université de Poitiers, Inserm, Laboratoire de Neurosciences Expérimentales
et Cliniques, Poitiers, France; CHU de Poitiers, Poitiers, France.
(5)Université de Poitiers, Inserm, Laboratoire de Neurosciences Expérimentales
et Cliniques, Poitiers, France; Université de Bordeaux, CNRS, IMN, UMR, 5293,
Bordeaux, France.
(6)Université de Poitiers, Inserm, Laboratoire de Neurosciences Expérimentales
et Cliniques, Poitiers, France; NIMES UNIV, APSY-V, Nîmes, France. Electronic
address: .

Autism spectrum disorder (ASD) is characterized by persistent deficits in social
communication and the presence of restricted and repetitive behaviors. While ASD
has a neurodevelopmental origin, it remains a lifelong condition, yet little is
known about how its behavioral and neural features evolve across adulthood.
Here, we investigated behavioral, synaptic, and structural alterations across
the transition from early to mature adulthood in Cntnap2 knockout mice, a widely
used model of ASD. Using a longitudinal behavioral approach combined with
electrophysiological recordings and morphological analysis, we show that KO mice
exhibit increased stereotyped and repetitive behaviors and reduced exploratory
activity at both ages. However, detailed analysis of behavioral patterns
revealed age-dependent differences, with early adult KO mice displaying
increased behavioral persistence that later evolved into distinct patterns of
behavioral sequences. These behavioral changes were associated with alterations
in inhibitory synaptic transmission in the dorsolateral striatum (DLS),
including changes in spontaneous inhibitory postsynaptic current (sIPSC)
frequency and temporal structure. In parallel, mature adult KO mice showed
structural remodeling of spiny projection neurons, characterized by increased
distal dendritic arborization and age-dependent organization of dendritic
spines. Together, our findings demonstrate that ASD-related alterations are not
static but evolve across adulthood, revealing a multi-level reorganization of
behavioral, synaptic, and structural features. These results highlight the
importance of considering adulthood stages in ASD and provide new insights into
the dynamic nature of the condition.

DOI: 10.1016/j.nbd.2026.107558
PMID: 42542171

Conflict of interest statement: Declaration of competing interest The authors
declare the following financial interests/personal relationships which may be
considered as potential competing interests: Mathieu Thabault reports financial
support was provided by European Commission. Mathieu Thabault reports article
publishing charges was provided by University College Cork. Laurie Galvan
reports financial support was provided by Fyssen Foundation. If there are other
authors, they declare that they have no known competing financial interests or
personal relationships that could have appeared to influence the work reported
in this paper.